Pyrrolo[1,2-b][1,2,4]oxadiazine diones useful as nitric oxide synthase inhibitors

ABSTRACT

The current invention discloses useful bicyclic and tricyclic amidino derivative compounds, pharmaceutical compositions containing these novel compounds, and to their use as nitric oxide synthase inhibitors.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to heteroatom containing monocyclicand bicyclic compounds, pharmaceutical compositions containing thesenovel compounds, and to their use in therapy, in particular their use asnitric oxide synthase inhibitors.

[0003] 2. Discussion of the Prior Art

[0004] It has been known since the early 1980's that the vascularrelaxation caused by acetylcholine is dependent on the presence of thevascular endothelium and this activity was ascribed to a labile humoralfactor termed endothelium-derived relaxing factor (EDRF). The activityof nitric oxide (NO) as a vasodilator has been known for well over 100years. In addition, NO is the active component of amylnitrite,glyceryltrinitrate and other nitrovasodilators. The recentidentification of EDRF as NO has coincided with the discovery of abiochemical pathway by which NO is synthesized from the amino acidL-arginine by the enzyme NO synthase.

[0005] Nitric oxide is the endogenous stimulator of the solubleguanylate cyclase. In addition to endothelium-dependent relaxation, NOis involved in a number of biological actions including cytotoxicity ofphagocytic cells and cell-to-cell communication in the central nervoussystem (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715,1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991).Excess NO production appears to be involved in a number of pathologicalconditions, particularly conditions which involve systemic hypotensionsuch as toxic shock, septic shock and therapy with certain cytokines(Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995).

[0006] The synthesis of NO from L-arginine can be inhibited by theL-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and thetherapeutic use of L-NMMA for the treatment of toxic shock and othertypes of systemic hypotension has been proposed (WO 91/04024 andGB-A-2240041). The therapeutic use of certain other NO synthaseinhibitors apart from L-NMMA for the same purpose has also been proposedin WO 91/04024 and in EP-A-0446699.

[0007] It has recently become apparent that there are at least threetypes of NO synthase as follows:

[0008] (i) a constitutive, Ca++/calmodulin dependent enzyme, located inthe endothelium, that releases NO in response to receptor or physicalstimulation.

[0009] (ii) a constitutive, Ca++/calmodulin dependent enzyme, located inthe brain, that releases NO in response to receptor or physicalstimulation.

[0010] (iii) a Ca++ independent enzyme which is induced after activationof vascular smooth muscle, macrophages, endothelial cells, and a numberof other cells by endotoxin and cytokines. Once expressed this inducibleNO synthase generates NO continuously for long periods.

[0011] The NO released by the two constitutive enzymes acts as atransduction mechanism underlying several physiological responses. TheNO produced by the inducible enzyme is a cytotoxic molecule for tumorcells and invading microorganisms. It also appears that the adverseeffects of excess NO production, in particular pathological vasodilationand tissue damage, may result largely from the effects of NO synthesizedby the inducible NO synthase (Knowles and Moncada, Biochem J., 298,249-258, 1994 Billiar et al., Annals of Surgery, 221, 339-349, 1995;Davies et al., 1995).

[0012] There is also a growing body of evidence that NO may be involvedin the degeneration of cartilage which takes place in certain conditionssuch as arthritis and it is also known that NO synthesis is increased inrheumatoid arthritis and in osteoarthritis (McInnes et al., J. Exp. Med,184, 1519-1524, 1996; Sakurai et al., J. Clin. Investig., 96, 2357-2363,1995). Accordingly, conditions in which there is an advantage ininhibiting NO production from L-arginine include autoimmune and/orinflammatory conditions affecting the joints, for example arthritis, andalso inflammatory bowel disease, cardivascular ischemia, diabetes,diabetic retinopathy, nephropathy, cardiomyopathy, congestive heartfailure, myocarditis, atherosclerosis, migraine, reflux esophagitis,diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma,chronic obstructive pulmonary disease, bronchiectasis, herniatedvertebral discs, obesity, psoriasis, rosacea, contact dermatitis,hyperalgesia (allodynia), cerebral ischemia [both focal ischemia,thrombotic stroke and global ischemia (secondary to cardiac arrest)],anxiety multiple sclerosis and other central nervous system disordersmediated by NO, for example Parkinson's disease and Alzheimer's disease,rhinitis, cancer therapy, and other disorders mediated by NO includingopiate tolerance in patients needing protracted opiate analgesics, andbenzodiazepine tolerance in patients taking benzodiazepines, and otheraddictive behavior, for example, nicotine and eating disorders (Kerwinet al., J. Medicinal Chemistry, 38, 4343-4362, 1995; Knowles andMoncada, Biochem J., 298, 249-258, 1994; Davies et al., 1995;Pfeilschifter et al., Cell Biology International, 20, 51-58, 1996).

[0013] Further conditions in which there is an advantage in inhibitingNO production from L-arginine-include systemic hypotension associatedwith septic and/or toxic shock induced by a wide variety of agents;therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant toshort term immunosuppression in transplant therapy (E. Kelly et al., J.Partent. Ent. Nutri., 19, 234-238, 1995; S. Moncada and E. Higgs, FASEBJ., 9, 1319-1330, 1995; R. G. Kilbourn et al, Crit. Care Med., 23,1018-1024, 1995).

[0014] More recently, NO has been identified as being a neurotransmitterin pain pathways of the spinal cord. The administration of NO synthaseinhibitors in patients with cronic pain syndromes, and more specificallycronic tension-type headaches, has been shown to reduce the level ofpain. (The Lancet, 353:256-257, 287-289)

[0015] Some of the NO synthase inhibitors proposed for therapeutic useso far, and in particular L-NMMA, are non-selective; they inhibit boththe constitutive and the inducible NO synthases. Use of such anon-selective NO synthase inhibitor requires that great care be taken inorder to avoid the potentially serious consequences of over-inhibitionof the constitutive NO-synthase including hypertension and possiblethrombosis and tissue damage. In particular, in the case of thetherapeutic use of L-NMMA for the treatment of toxic shock it has beenrecommended that the patient must be subject to continuous bloodpressure monitoring throughout the treatment. Thus, while non-selectiveNO synthase inhibitors have therapeutic utility provided thatappropriate precautions are taken, NO synthase inhibitors which areselective in the sense that they inhibit the inducible NO synthase to aconsiderably greater extent than the constitutive isoforms of NOsynthase would be of even greater therapeutic benefit and easier to use(S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).

[0016] WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231WO 95/25717, WO 95/24382, WO94/12165, WO94/14780, WO93/13055,EP0446699A1 and U.S. Pat. No. 5,132,453 disclose compounds that inhibitnitric oxide synthesis and preferentially inhibit the inducible isoformof nitric oxide synthase. The disclosures of which are herebyincorporated by reference in their entirety as if written herein.

SUMMARY OF THE INVENTION

[0017] In accordance with the present invention novel heterocyclicbicyclic derivatives are provided. These novel inhibitor compounds arerepresented by the following formula

[0018] and salts, pharmaceutically acceptable esters, and prodrugsthereof, wherein:

[0019] R¹ is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, C(O)R⁶,carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon and cycloalkyl, allof which may be optionally substituted by one or more of the groupsselected from lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,heterocyclyl, aryl, halogen, cyano, nitro, amino, alkylamino,dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl,alkylaminoaryl, acylamino, carboxy, carboxyalkyl, P(R⁵)₃, C(O)R⁵, OR⁵,SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substituents maybe optionally substituted with one or more selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), C(O)R⁶, carboalkoxyalkyl, cyano, nitro, amidino, andguanidino, wherein R⁵ and R⁶ of SO₂NR⁵R⁶ and NR⁵SO₂R⁶ may be takentogether to form a N-containing heterocycle, optionally substituted byone or more selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano,nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, andcarboxyalkyl;

[0020] R¹ may be

[0021] wherein J is selected from the group consisting of O, S and NR;

[0022] R is selected from the group consisting of hydrogen, lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle,aromatic hydrocarbon, alkylaryl, alkylheterocycle, all of which may beoptionally substituted by one or more of alkyl, hydroxy, alkoxy,halogen, haloalkyl, cyano, amino, and nitro;

[0023] NR and R²⁰ may optionally form a heterocycle;

[0024] R¹⁶ is selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano,nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl,C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵, S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substituents maybe optionally substituted with one or more of the group consisting oflower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lowerthioalkoxy, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, S(O)R⁸,S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂, PO(OR⁸)(OR⁹), amidino, andguanidino;

[0025] R¹⁷ is selected from the group consisting of hydrogen, loweralkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle,aromatic hydrocarbon, alkylaryl, and alkylheterocycle, all excepthydrogen may be optionally substituted by one or more of alkyl, hydroxy,alkoxy, thiol, alkylthiol, halogen, haloalkyl, carboxyl, cyano, amino,and nitro;

[0026] R¹⁸ is selected from the group consisting of hydrogen, hydroxyl,R¹², S(O)R¹¹, SO₂R¹¹, CH₂OC(O)—R¹¹, and C(O)—R¹¹ wherein C(O)—R¹¹;

[0027] R¹⁸ and R²⁰ may be taken together to form a 5- or 6-memberedheterocyclic ring containing two or more heteroatoms which may beoptionally substituted by one or more of R¹⁶;

[0028] R² and L may be taken together to form a 3 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶;

[0029] R² and R¹⁷ may be taken together to form a 4 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶;

[0030] R² and R¹⁸ may be taken together to form a 6 to 9 memberedheterocyclic ring which may be optionally substituted by one or more ofR¹⁶;

[0031] L and R¹⁷ may be taken together to form a 3 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶;

[0032] L and R¹⁸ may be taken together to form a 4 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶;

[0033] R¹⁷ and R¹⁸ and may be taken together to form a 4 to 9 memberedheterocyclic ring which may be optionally substituted by one or more ofR¹⁶;

[0034] R¹⁷ and Q may be taken together to form a 3 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶;

[0035] R¹⁸ and Q may be taken together to form a 4 to 9 memberedheterocyclic ring which may be optionally by one or more of R¹⁶;

[0036] R¹⁷ and R²⁰ and may be taken together to form a 5 to 9 memberedheterocyclic ring which may be optionally substituted by one or more ofR¹⁶;

[0037] R¹⁹ is hydrogen, R¹¹, or C(O)—R¹¹;

[0038] R¹¹ is selected from the group consisting of hydrogen, hydroxyl,alkenyl, alkynyl, heterocyclyl, aromatic hydrocarbon, cycloalkyl,dihydropyridyl, alkyl, alkylthiol, alkoxy, amino, and cycloalkoxy, whichmay be optionally substituted with one or more of amino, carboxyl,carboxamide, thioalkyl, aromatic hydrocarbon, alkyl, alkylaryl, hydroxy,alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, heterocyclyl,alkylheterocycle, and alkylthiol, which may be optionally substitutedwith one or more of hydroxy, amino, guanidino, iminoalkyl;

[0039] R¹² is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocycle, and aromatic hydrocarbon, allmay be optionally substituted by one or more alkyl, hydroxy, alkoxy,halogen, trifluoromethyl, nitro, cyano, or amino groups;

[0040] R²⁰ is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aromatichydrocarbon, heterocycle, alkylaryl, and alkylheterocycle, which may beoptionally substituted by one or more of halogen, haloalkyl, cyano,nitro, —CO₂R, and —COR;

[0041] R²⁰ may also be selected from the group consisting ofalkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyacyl, CH₂C(═O)OR¹²,CH₂C(═O)NHR¹², CH₂OC(═O)R¹², and CH₂OC(═O)VR¹², wherein the CH₂ may beoptionally substituted by one or more of lower alkyl, cycloalkyl,heterocycle, aromatic hydrocarbon, amidino, guanidino, CO₂H, amino,hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;

[0042] V is selected from the group consisting of O, S, CH₂, CHR¹²,C(R¹²)₂, NH, and NR¹²;

[0043] R², R³, R⁴ are independently selected from the group consistingof hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aromatichydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶, PO(OR⁵)(OR⁶),halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino, carboxyl,carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substitutions maybe optionally substituted with one or more of the group consisting oflower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lowerthioalkoxy, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, andguanidino;

[0044] G is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(p), and CH═CH, wherein p is 0 to 6;

[0045] A is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(q), and CH═CH, q is 0 to 6;

[0046] B is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(v), and CH═CH. v is0 to 6;

[0047] R¹ and R² may optionally be taken together to form an alicyclichydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionallyformed ring may be optionally substituted with one or more selected fromthe group consisting of lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷,SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino;

[0048] R² and R³ may optionally be taken together to form an alicyclichydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionallyformed ring may be optionally substituted with one or more selected fromthe group consisting of, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen,cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino, whereinall said substitutions may be optionally substituted with one or more ofthe group consisting of lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy,aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂,PO(OR⁵)(OR⁶), amidino, and guanidino.

[0049] L and Q are independently selected from the group consisting oflower alkylene, lower alkenylene, lower alkynylene, heterocyclyl,cycloalkyl, aromatic hydrocarbon, and —(CH₂)_(m)—M—(CH₂)_(n)—,—(CH₂)_(k)—, wherein all said substituents may optionally be substitutedby one or more lower alkyl, lower alkenyl, lower alkynyl, C(O)R⁶,carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵,heterocyclyl, halogen, nitro, cyano, haloalkyl, cycloalkyl,heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino,isourea, isothiourea, guanidino, and substituted guanidino;

[0050] k is 0 to 8;

[0051] m is 0 to 7;

[0052] n is 0 to 5;

[0053] M is selected from the group consisting of cycloalkyl,heterocyclyl, aromatic hydrocarbon, O, S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵,POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵, C(O), C(O)O, Se, SeO, SeO₂,C(O)NR¹³, and SiE₂, wherein R¹³ is selected from the group consisting ofhydrogen, lower alkyl, alkaryl, heterocyclyl, COR¹⁴, and CO₂R¹⁴ whereinR¹⁴ is lower alkyl or aromatic hydrocarbon;

[0054] E is lower alkyl or aryl;

[0055] L and R² may be taken together to form a lower alkylidene;

[0056] R⁵ is selected from the group consisting of hydrogen, halogenlower alkyl, aromatic hydrocarbon, and alkylaryl, wherein all saidsubstituents may be optionally substituted by one or more carboalkoxy,thiol, amino, hydroxyl, carboxyl, lower alkyl, lower alkenyl, loweralkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides, phosphonates,and sulfonates;

[0057] R⁶ is selected from the group consisting of hydrogen, loweralkyl, aromatic hydrocarbon and alkylaryl wherein all said substituentsmay be optionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;

[0058] R⁷ is selected from the group consisting of hydroxy, alkoxy, andaryloxyl;

[0059] X is selected from the group consisting of O, S, C(═O), C(═S),C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂;

[0060] Y is a bond, or is selected from the group consisting of O, S,C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂;

[0061] Z is selected from the group consisting of O, S, C(═O), C(═S),C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂.

[0062] More preferred embodiments of the invention are shown in theclaims.

[0063] In another broad aspect, the present invention is directed toinhibiting nitric oxide synthesis in a subject in need of suchinhibition or treatment by administering a compound of Formulas I and IIwhich preferentially inhibits the inducible isoform of nitric oxidesynthase over the constitutive isoform of nitric oxide synthase, in anitric oxide synthesis inhibiting amount to such subject.

[0064] The invention further relates to a pharmaceutical compositioncomprising a compound from Formulas I and II.

[0065] Conditions in which there is an advantage in inhibiting NOproduction from L-arginine in disorders mediated by nitric oxide includeamongst others, disorders involving systemic hypotension associated withseptic and/or toxic shock induced by a wide variety of agents; therapywith cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to shortterm immunosuppression in transplant therapy. Further conditions inwhich there is an advantage in inhibiting NO production from L-arginineinclude autoimmune diseases and/or inflammatory conditions such as thoseaffecting the joints, for example arthritis or inflammatory boweldisease, cardiovascular ischemia, diabetes, congestive heart failure,myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea,irritable bowel syndrome, cystic fibrosis, emphysema, hyperalgesia(allodynia) cerebral ischemia (both focal ischemia, thrombotic strokeand global ischemia, secondary to cardiac arrest) and other CNS disordermediated by NO, including opiate tolerance in patients needingprotracted opiate analgesics, benzodiazepine tolerance in patientstaking benzodiazepines, and other addictive behaviors for examplenicotine and eating disorder.

[0066] The present invention includes compounds of Formulas I and II inthe form of salts, in particular acid addition salts. Suitable saltsinclude those formed with both organic and inorganic acids. Such acidaddition salts will normally be pharmaceutically acceptable althoughsalts of non-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulfuric, citric, tartaric, phosphoric, lactic, acetic, succinic,fumaric, maleic, methanesulfonic, ethanesulfonic, p-toluenesulfonic,benzenesulfonic and the like. (See, for example, S. M. Berge et al.,Pharmaceutical Salts, J. Pharm. Sci., 1977, 66, 1-19.) Salts of thecompounds of Formula I can be made by reacting the appropriate compoundin the form of the free base with the appropriate acid.

[0067] While it may be possible for the compounds of Formulas I and IIto be administered as the raw chemical, it is preferable to present themas a pharmaceutical formulation. According to a further aspect, thepresent invention provides a pharmaceutical formulation comprising acompound of Formulas I and II or a pharmaceutically acceptable salt orsolvate thereof, together with one or more pharmaceutically acceptablecarriers thereof and optionally one or more other therapeuticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

[0068] The formulations include those suitable for oral, inhalation,parenteral (including subcutaneous, intradermal, intramuscular,intravenous and intraarticular), rectal and topical (including dermal,buccal, sublingual and intraocular) administration although the mostsuitable route may depend upon for example the condition and disorder ofthe recipient. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. All methods include the step of bringing intoassociation a compound of Formulas I and II or a pharmaceuticallyacceptable salt or solvate thereof (“active ingredient”) with thecarrier which constitutes one or more accessory ingredients. In general,the formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

[0069] Formulations of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

[0070] A tablet may be made by compression or molding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

[0071] Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain antioxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example, saline, water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

[0072] Formulations for rectal administration may be presented as asuppository with the usual carriers such as cocoa butter or polyethyleneglycol.

[0073] Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

[0074] Formulations for inhalation administration where the activeingredient is inhaled into the lungs either as a mist or co-administeredwith an inert carrier agent.

[0075] Preferred unit dosage formulations are those containing aneffective dose, as hereinbelow recited, or an appropriate fractionthereof, of the active ingredient.

[0076] It should be understood that in addition to the ingredientsparticularly mentioned above, the formulations of this invention mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

[0077] The compounds of the invention may be administered orally or viainjection at a dose of from 0.001 to 2500 mg/kg per day. The dose rangefor adult humans is generally from 0.005 mg to 10 g/day. Tablets orother forms of presentation provided in discrete units may convenientlycontain an amount of compound of the invention which is effective atsuch dosage or as a multiple of the same, for instance, units containing5 mg to 500 mg, usually around 10 mg to 200 mg.

[0078] The compounds of Formulas I and II are preferably administeredorally or by injection (intravenous or subcutaneous). The precise amountof compound administered to a patient will be the responsibility of theattendant physician. However, the dose employed will depend on a numberof factors, including the age and sex of the patient, the precisedisorder being treated, and its severity. Also, the route ofadministration may vary depending on the condition and its severity.

[0079] The term “lower alkyl”, alone or in combination, means an acyclicalkyl radical containing from 1 to about 10, preferably from 1 to about8 carbon atoms and more preferably 1 to about 6 carbon atoms. Examplesof such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and thelike.

[0080] The term “lower alkenyl” refers to an unsaturated acyclichydrocarbon radical in so much as it contains at least one double bond.Such radicals containing from about 2 to about 10 carbon atoms,preferably from about 2 to about 8 carbon atoms and more preferably 2 toabout 6 carbon atoms. Examples of suitable alkenyl radicals includepropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl,2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, andocten-1-yl, and the like.

[0081] The term “lower alkynyl” refers to an unsaturated acyclichydrocarbon radical in so much as it contains one or more triple bonds,such radicals containing about 2 to about carbon atoms, preferablyhaving from about 2 to about 8 carbon atoms and more preferably having 2to about 6 carbon atoms. Examples of suitable alkynyl radicals includeethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl,3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl,3,3-dimethylbutyn-1-yl radicals and the like.

[0082] The term “alicyclic hydrocarbon” or “cycloalkyl” means aaliphatic radical in a ring with 3 to about 10 carbon atoms, andpreferably from 3 to about 6 carbon atoms. Examples of suitablealicyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl and the like.

[0083] The term “aromatic hydrocarbon” means and unsaturated cyclic orplycyclic radical with 4 to about 16 carbon atoms, preferably 6 to about12 carbon atoms, more preferably 6 to about 10 carbon atoms. Examples ofsuitable aromatic hydrocarbon radicals include phenyl, naphthyl,thienyl, furanyl, pyridinyl, (is)oxazoyl and the like.and the like.

[0084] The term “DCM” means dichloromethane.

[0085] The term “DEAD” means diethyl azodicarboxylate.

[0086] The term “DIBAL-H” means diisobutylaluminum hydride.

[0087] The term “DMAP” means dimethylaminopyridine.

[0088] The term “DMSO” means dimethylsulfoxide.

[0089] The term “EDC” means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0090] The term “heterocyclyl” means a saturated or unsaturated cyclichydrocarbon radical including aromatic systems with 4 to about 10 carbonatoms, preferably about 5 to about 6; wherein 1 to about 4 carbon atomsare replaced by nitrogen, oxygen, sulfur, or carbonyl. The “heterocyclicradical” may be fused to an aromatic hydrocarbon radical. Suitableexamples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl,pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, indolyl,thienyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl,1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,pyrazolidinyl, isoxazolinyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl,triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl,quinolinyl, and the like.

[0091] The term “HOBT” means N-hydroxybenzotriazole.

[0092] The term “lower alkoxy”, alone or in combination, means an alkylether radical wherein the term alkyl is as defined above and mostpreferably containing 1 to about 4 carbon atoms. Examples of suitablealkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

[0093] The term “lower thioalkoxy”, alone or in combination, means analkyl thioether radical wherein the term alkyl is as defined above andmost preferably containing 1 to about 4 carbon atoms. Examples ofsuitable alkyl thioether radicals include thiomethoxy, thioethoxy,thio-n-propoxy, thio-i-propoxy, thio-n-butoxy, thio-iso-butoxy,thio-sec-butoxy, thio-tert-butoxy and the like.

[0094] The term “alkoxycarbonyl” as used herein means an alkoxy group,as defined above, having a carbonyl (C═O) group attached.

[0095] The term “halogen” means fluorine, chlorine, bromine or iodine.

[0096] The term “MCPBA’ means m-chloroperbenzoic acid.

[0097] The term “NMM” means N-methylmorpholine.

[0098] The term “NMMO” means 4-methylmorpholine N-oxide.

[0099] The term “prodrug” refers to a compound that is made more activein vivo.

[0100] The term “sulfinyl” means SO.

[0101] The term “sulfonyl” means SO₂.

[0102] The term “TEA” means triethylamine.

[0103] The term “TMSN₃” means azidotrimethylsilane.

[0104] As used herein, reference to “treatment” of a patient is intendedto include prophylaxis.

[0105] All references, patents or applications, U.S. or foreign, citedin the application are hereby incorporated by reference as if writtenherein.

[0106] Compounds of the present invention can exist in geometric orstereoisomeric forms. The present invention contemplates all suchcompounds, including cis- and trans-geometric isomers, E- andZ-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers,l-isomers, the racemic mixtures thereof and other mixtures thereof, asfalling within the scope of the invention.

[0107] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the following preferredspecific embodiments are to be construed as merely illustrative and notlimitative of the remainder of the disclosure in any way whatsoever.

[0108] All experiments were performed under either dry nitrogen orargon. All solvents and reagents were used without further purificationunless otherwise noted. The routine work-up of the reactions involvedthe addition of the reaction mixture to a mixture of either neutral, oracidic, or basic aqueous solutions and organic solvent. The aqueouslayer was extracted n times (x) with the indicated organic solvent. Thecombined organic extracts were washed n times (x) with the indicatedaqueous solutions, dried over anhydrous Na₂SO₄, filtered, concentratedin vacuo, and purified as indicated. Separations by columnchromatography were achieved with conditions described by Still. (Still,W. C.; Kahn, M.; Mitra, A. Rapid Chromatograhic Technique forPreparative Separation with Moderate Resolution. J. Org. Chem., 1978,43, 2923-2925.) The hydrochloride salts were made from 1N HCl, HCl inethanol (EtOH), 2 N in MeOH, or 6 N HCl in dioxane. Thin layerchromatograms were run on 0.25 mm EM precoated plates of silica gel 60F254. High performance liquid chromatograms (HPLC) were obtained fromC-8 or C-18 reverse phase columns which were obtained from severalvendors. Analytical samples were dried in an Abderhalden apparatus ateither 56_C or 78_C. ¹H NMR spectra were obtained from either GeneralElectric QE-300 or Varian VXR 400 MHz spectrometer withtetramethylsilane as an internal standard. ¹³C NMR were obtained from aVarian spectrometer at 125.8 MHz with tetramethylsilane as an internalstandard.

Schemes

[0109] Disclosed are twenty two general synthetic processes useful inthe preparation of the compounds of the present invention.

EXAMPLE 1 6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0110]

[0111] To a solution of 2 g (16 mmol) of 2-hydroximinohomopiperidine(Maybridge) in 20 mL of methylene chloride (CH₂Cl₂) was added 2.5 g (16mmol) of 1,1′-carbonyldiimidazole (CDI). This was stirred at 25° C. forsix days. This solution was diluted with CH₂Cl₂, washed with water,dried (MgSO₄), filtered and concentrated to afford 2.2 g (89% yield) ofthe title compound as a white semi-solid.

[0112] Mass Spectra for C₇H₁₀N₂O₂: M⁺H=155.

[0113]¹H NMR (CDCl₃) d 1.5-1.9 (m, 6H), 2.6 (dd, 2H), 3.6 (dd, 2H).

[0114]¹³C NMR (CDCl₃) d 25.3, 26.0, 28.2, 30.2, 43.7, 159.1, 161.6.

EXAMPLE 2 1,1-dimethylethyl[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]carbamate

[0115]

[0116] Ex-2a) A mixture of sodium acetate (6.4 g, 78 mmol) and aceticanhydride (30 mL, 330 mmol) was stirred at 0-5° C. To this slurry wasadded 2-nitroethanol (30 g, 280 mmol) dropwise over a period ofapproximately 1 hour. After the 2-nitroethanol addition, the orangereaction mixture was stirred at 0-5° C. for an additional hour and thenat ambient temperature for approximately 70 min, the exotherm of thereaction increased the temperature to 30° C. and the mixture was cooledwith an ice bath to 20° C. The reaction was then stirred at ambienttemperature under N₂ overnight. The reaction mixture was diluted withethyl acetate (EtOAc, 40 mL) and saturated brine (80 mL). The layerswere separated and the bottom aqueous layer was extracted again withethyl acetate (25 mL). The combined ethyl acetate layers were washedonce with saturated brine (50 mL), dried (MgSO₄), filtered andconcentrated to afford 38 g of 2-nitroethylacetate as a reddish orangeoil.

[0117] Ex-2b) To a solution of 1-morpholino-1-cyclohexene (51 g; 300mmol) in 120 mL anhydrous acetonitrile at 0-4° C. was added the2-nitroethylacetate product of Example 2a (37.8 g, 293 mmol) dropwise.The resulting red solution was stirred under N₂ atmosphere in an icebath for 2½ hrs. The red solution was then stirred at ambienttemperature under an N₂ atmosphere overnight. Water (100 mL) was addedto the red solution over a 10-15 minute period. The temperature rosefrom 20 to 29° C. with the first 200 mL of water, but then dropped to27° C. by the end of the addition. This was then acidified with aqueousHCl. The dark red reaction mixture was diluted with 85 mL of EtOAc andthe layers separated. The light orange water layer (bottom) wasextracted again with 50 mL of EtOAc. The combined EtOAc layers werewashed with saturated brine (2×85 mL), dried (MgSO₄), filtered andconcentrated to afford 45 g of 2-(2-nitroethyl)cyclohexanone as a redoil.

[0118] Ex-2c) To a solution of hyroxylamine-0-sulfonic acid (9.9 g; 86mmol) in 17 mL of 96% formic acid was added the product of Example 2b(13.7 g; 88 mmol) in 5 mL of 96% formic acid dropwise at 60-65° C. overa period of 65 minutes. After the addition, the temperature was slowlyraised in 10° C. increments. An exotherm was observed at around 85-90°C. After the exotherm subsided (35 min), the dark brownish red mixturewas heated gently at reflux for 1 hr. After cooling to room temperature,the dark brown red reaction mixture was slowly poured into water. Thesolution was cooled to produce a heavy precipitate. Filtration afforded5.7 g of 7-(2-nitroethyl)caprolactam as a brown solid. mp=140-141° C.

[0119] Ex-2d) The product of Example 2c was allowed to react withpalladium black and ammonium formate in methanol to afford2-(2-aminoethyl)caprolactam.

[0120] Ex-2e) The product of Example 2d was allowed to react with Bocanhydride to afford 2-(2-Boc-aminoethyl)caprolactam.

[0121] Ex-2f) A portion of the product of Example 2e (1 g, 4 mmol) wasallowed to react with 0.74 g (5 mmol) of trimethyloxoniumtetrafluoroborate in 25 mL CH₂Cl₂ over a 16 hour period. The mixture wasdiluted with 100 mL CH₂Cl₂ and washed with 2×50 mL 5% NaHCO₃ and 100 mLbrine. The organic phase was dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0122] Ex-2g) The product of Example 2e (0.67 g, 2.48 mmol) was allowedto react with 0.207 g (3 mmol) of hydroxylamine hydrochloride in 25 mLMeOH for 16 hours. The methanol was evaporated to afford thehydroxamidine as an oil.

[0123] Ex-2) The product of Example 2g was allowed to react with 0.49 g(3 mmol) of 1,1′-carbonyldiimidazole in 25 mL of CH₂Cl₂ for 24 hours atroom temperature. The title compound is isolated from the reactionmixture using C₁₈ reverse phase HPLC (10-50% acetonitrile gradient in 30minutes).

EXAMPLE 35-(2-aminoethyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one,mono(trifluoroacetate)

[0124]

[0125] Ex-3) The product of Example 2 was treated with 10 mLtrifluoroacetic acid for 15 minutes to remove the Boc-protecting group.The solvent was evaporated in vacuo and title compound was isolated viaC₁₈ reversed phase HPLC (0-40% acetonitrile gradient in 30 minutes) toyield 100 mg of the title material.

[0126] Mass Spectra for C₁₁H₁₆F₃N₃O₄: M⁺H=198.

[0127]¹H NMR (D₂O): d 1.25-2.20 (m; 8H), 2.48-2.62 (m; 1H), 2.75-3.04(m; 3H), 4.10-4.22 (m; 1H).

[0128] Elemental analysis for C₇H₁₀N₂O₂: Calcd. C, 42.45 H, 5.18 N,13.50 Found: C, 40.93 H, 5.43 N, 11.91

EXAMPLE 4 methyl6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-carboxylate

[0129]

[0130] Ex-4a) To a solution of 7-methylcarboxylate caprolactam (9.78 g,57 mmol) in CH₂Cl₂ at room temperature was added trimethyloxoniumtetrafluoroborate (9.30 g, 63 mmol). This solution was stirred for 16hours at 25° C. The solution was then washed twice with sodiumbicarbonate and twice with brine, dried over magnesium sulfate andstripped of all solvent under reduced pressure to yield the iminoetheras a light yellow colored oil.

[0131] Mass Spectra of C₉H₁₅N₁O₃: M⁺H=186.

[0132]¹H NMR (CDCl3) d 3.96-3.98 (d, 1H), 3.6 (s, 3H), 3.5 (s, 3H)2.2-2.3 (m, 2H), 1.8-1.9 (m, 2H), 1.4-1.5 (m, 4H), 1.1-1.2 (m, 1).

[0133]¹³C NMR (CDCl3) d 174.5, 168.9, 61.7, 52.7, 51.8, 32.2, 30.9,29.6, 22.9.

[0134] Ex-4b) To a solution of the product of Example 4a in methanol wasadded hydroxylamine hydrochloride (4.81 g, 69 mmol). The solution wasstirred for 6 hours before the solvent was removed under pressure toyield the oxime.

[0135] Mass Spectra for C₈H₁₄N₂O₃: M⁺H=187.

[0136]¹³C NMR (CDCl3) d 170.4, 162.9, 56.9, 53.5, 32.0, 28.4, 25.0,23.5.

[0137] Ex-4) To a solution of the product of Example 4b in CH₂Cl₂ wasadded CDI (11.2 g, 69 mmol). This solution was stirred for 16 hours at25° C. The solution was then washed twice with potassium hydrogensulfate and twice with brine. All solvent was removed under reducedpressure to yield the title compound.

[0138] Mass Spectra for C₉H₁₂N₂O₄: M⁺H=212.

[0139]¹³C NMR (CDCl3) d 169.2, 161.0, 159.1, 56.2, 53.3, 30.6, 26.6,26.3, 25.0.

EXAMPLE 56,7,8,9-tetrahydro-5-(hydroxymethyl)-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0140]

[0141] Ex-5) To a solution of the product of Example 4 in anhydrous THFwas added lithium borohydride (21.5 mL, 43 mmol). This solution wasstirred for 16 hours at 25° C. The lithium borohydride was quenched withmethanol and the solvent was removed under reduced pressure. The residuewas dissolved in ethyl acetate, washed twice with potassium hydrogensulfate and twice with brine. The organic phase was dried over magnesiumsulfate and all solvent was removed under reduced pressure to yield thetitle compound.

[0142] Mass Spectra for C₈H₁₂N₂O₃: M⁺H=184.

[0143]¹H NMR (CDCl₃) d 4.1-4.2 (m, 1H), 3.8 (d, 2H), 3.1 (s, 1H),2.8-2.9 (m, 1H), 2.6-2.7(m, 1H), 2.1-2.2 (m, 1H), 1.9-2.0(m, 1H),1.7-1.8(m, 3H), 1.4-1.6(m, 1H).

[0144]¹³C NMR (CDCL₃) d 161.1, 160.1, 62.2, 56.4, 29.5, 25.9, 25.2,25.0.

EXAMPLE 66,7,8,9-tetrahydro-5-(2-propenyl)-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0145]

[0146] EX-6a) A suspension of potassium t-butoxide (200 g, 1.78 mol) intoluene which was cooled to 0° C. in an ice bath under N₂ was treatedwith cyclohexanone (157 g, 1.60 mol). To the reaction mixture was slowlyadded allyl bromide (194 g, 1.60 mol) over a 2 hour period. The reactionwas warmed to room temperature over 5 hours. The reaction was thenpoured into EtOAc (400 mL) and washed once with 10% potassium hydrogensulfate (250 mL). The organic solution was then washed with brine (3×200mL), dried over magnesium sulfate, and evaporated under reducedpressure. The resulting oil was then chromatographed to yield 158.4 g(71.6%) of 2-allyl cyclohexanone as an oil.

[0147]¹H NMR (CDCl₃, 300 MHz) d 1.2-2.5 (m, 10H), 2.59 (m, 1H), 5.0 (dd,2H), 5.75 (m, 1H).

[0148]¹³C NMR (CDCl₃, 75 MHz) d 25.04, 28.03, 33.46, 33.86, 42.12,50.35, 116.3, 136.6, 212.5.

[0149] EX-6b) A solution of the product of Example 6a (56.4 g, 0.408mol) in formic acid (200 mL) was stirred under N₂ for 5 minutes. To thissolution was added hydroxylamine-O-sulfonic acid (53.0 g, 0.448 mol).The reaction was stirred at reflux for 45 minutes before the solvent wasremoved under reduced pressure. Ethyl acetate was poured into theresulting black slurry and the mixture was neutralized with a solutionof saturated sodium bicarbonate until the evolution of gas ceased. Theorganic layer was separated, washed with brine (3×150 mL), dried overmagnesium sulfate and stripped of solvent under reduced pressure. Theresulting dark brown solid was chromatographed with 1:1 ethylacetate:hexane to afford 18.5 g (30%) of the lactam as a cream coloredsolid.

[0150]¹H NMR (CDCl₃, 300 MHz) d 1.25 (m, 2H), 1.42 (m, 2H), 1.86 (m,2H), 2.15 (m, 2H), 2.33 (m, 2H), 3.28 (m, 2H), 5.04 (dd, 2H), 5.64 (m,1H) 6.07 (bs, 1H).

[0151]¹³C NMR (CDCl₃, 75 MHz) d 23.30, 29.87, 35.51, 37.14, 40.66,53.05, 118.9, 134.1, 177.9.

[0152] EX-6c) A solution of the product of Example 6b (20 g, 0.130 mol)in CH₂Cl₂ (200 mL) was stirred under a blanket of N₂ for 5 minutes. Tothe solution was added trimethyloxonium tetrafluoroborate (20 g, 0.135mol). The reaction was stirred at reflux for 2 hours while beingmonitored by thin layer chromatography and then cooled to roomtemperature. The reaction was neutralized with a solution of saturatedsodium bicarbonate. The organic layer was separated, washed with brine(3×100 mL), and dried over magnesium sulfate before all solvent wasremoved under reduced pressure to afford 20 g of the iminoether as anoil.

[0153] EX-6d) To a solution of the product of Example 6c (˜20 g) inmethanol (200 mL) under N₂ was added hydroxylamine hydrochloride (22.2g, 0.154 mol). The reaction was brought to reflux and stirred at refluxfor 2 hours before it was cooled to room temperature. The solvent wasremoved under reduced pressure and toluene was added to the oil residue.The toluene was then removed under reduced pressure to afford 20 g ofthe hydroxamidine as a cream colored solid.

[0154] EX-6) To a solution of the product of Example 6d (˜20 g) inCH₂Cl₂ (200 mL) under N₂ was added 1,1′-carbonyldiimidazole (22.7 g,0.140 mol) portionwise. The reaction was then stirred for 1 hour. To thereaction was added an additional portion of the 1,1′-carbonyldiimidazole(1 g, 0.00617 mol) to insure all starting material had reacted. To thereaction was then added a solution of 10% potassium hydrogensulfate (200mL). The organic was separated, washed with brine (3×100 mL), dried overmagnesium sulfate and stripped of all solvent under reduced pressure.The resulting solid was chromatographed (silica gel) with 1:1 ethylacetate:hexane to afford the title compound 8.0 g (31.5%).

[0155]¹H NMR (CDCl₃, 300 MHz) d 1.50-2.25 (m, 6H), 2.51 (m, 4H), 2.87(dd, 2H), 4.29 (m, 1H), 5.05 (dd, 2H), 5.75 (m, 1H).

[0156]¹³C NMR (CDCl₃, 75 MHz) d 23.97, 25.66, 26.32, 31.22, 36.52,53.45, 119.1, 133.0, 159.7, 160.7.

EXAMPLE 75-ethyl-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0157]

[0158] Ex-7a) A sample of 7-ethylcaprolactam (5 g, 35.4 mmol) wasallowed to react with 6.8 g (46.0 mmol) of trimethyloxoniumtetrafluoroborate in 120 mL CH₂Cl₂ over a 5 day period. The productiminoether (4.2 g) was obtained as a pale yellow oil from the reactionmixture by the methods of Example 2f.

[0159] Ex-7b) The product of Example 7a (4.2 g, 27.0 mmol) was allowedto react with 1.9 g (27.0 mmol) of hydroxylamine hydrochloride in 40 mLMeOH for 24 hours. The hydroxamidine product was obtained as an oil bythe methods of Example 2g.

[0160] Ex-7) The product of Example 7b is allowed to react1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature andthe title compound is isolated from the reaction mixture using C₁₈reverse phase HPLC as described in Example 2.

EXAMPLE 86,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-acetaldehyde

[0161]

[0162] EX-8) To a solution of the product of Example 6 in dioxane (200mL) and water (135 mL) was added sodium periodate (15.11 g, 0.071 mol)and osmium tetraoxide (12 drops of a 1 ppm solution of osmium dioxide inn-BuOH/H₂O). The reaction was stirred at room temperature and monitor bythin layer chromatography for one day. Since the starting material hadnot completely reacted, additional osmium tetraoxide (12 drops of 1 ppmsolution of osmium dioxide in n-BuOH/H₂O) was added. A white precipitatewas filtered off and the filtrate was removed under reduced pressure tothe point where no dioxane remained. Additional water (75 mL) was thenadded to the aqueous layer and this aqueous mixture was washed withCH₂Cl₂ (3×75 mL). The organic layer was combined, dried over magnesiumsulfate, and stripped of all solvent under reduced pressure to afford ayellow oil. Chromatographic (silica gel) purification of this materialeluting with the 1:1, ethyl acetate:hexane afforded 4.0 g (67%) of thetitle compound.

[0163]¹H NMR (CDCl₃, 300 MHz) d 1.2-2.5 (m, 6H), 2.59 (q, 2H), 2.92 (m,2H), 4.79 (m, 1H), 9.79 (ss, 1H).

[0164]¹³C NMR (CDCl₃, 75 MHz) d 24.12, 31.52, 32.00, 45.61, 49.10,53.98, 159.9, 160.8, 198.1.

EXAMPLE 96,7,8,9-tetrahydro-5-(2-hydroxyethyl)-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0165]

[0166] To a solution of the product of Example 8 (3.0 g, 0.015 mol) intetrahydrofuran (20 mL) was added a borane.THF complex (20 mL, 0.020mol). The reaction stirred for 2 hours upon which methanol (19 mL) wasadded. The solvent was removed under reduced pressure. The resulting oilwas partioned between CH₂Cl₂ (40 mL) and water (2×20 mL). The organiclayer was dried over magnesium sulfate and all solvent was removed underreduced pressure. The residue was chromatographed eluting with 1:1 ethylacetate/hexane to produce 2.1 g (69%) of the title material.

[0167]¹H NMR (CDCl₃, 300 MHz) d 1.18-2.15(m, 8H), 3.59(m, 2H), 4.39(m,1H).

[0168]¹³C NMR (CDCl₃, 75 MHz) d 24.45, 25.71, 26.47, 32.56, 34.67,51.16, 58.85, 160.66, 160.89.

EXAMPLE 10 ethyl4,5-dihydro-5-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-3-isoxazolecarboxylate

[0169]

[0170] To a solution of 0.5 g (2.6 mmol) of the product of Example 6 in100 mL of toluene was added 0.8 g (5.2 mmol) of ethylchlorooximidoacetate (Aldrich). This solution was brought to reflux andstirred for 18 hours. All solvent was removed in vacuo and the residuepurified via C-18 chromatography (0-60% acetonitrile/water, 25 min.)with the product eluting at 54% acetonitrile. Concentration of therelevant fractions afforded 0.6 g (75% yield) of the title compound as apale yellow oil.

[0171] Mass Spectra for C₁₄H₁₉N₃O₅: M⁺H=310.

[0172]¹H NMR (CDCl₃) d 1.3 (t, 3H), 1.5 (bt, 1H), 1.7-2.2 (m, 7H), 2.5(m, 1H), 2.8-3.0 (m, 2H), 3.3-3.5 (m, 1H), 4.3 (q, 2H), 4.4 (m, 1H), 4.8(m, 1H).

[0173] Elemental analysis for C₁₄H₁₉N₃O₅+0.25 H₂O: Calcd: C, 53.58 H,6.26 N, 13.39. Found: C, 53.93 H, 6.16 N, 13.13.

EXAMPLE 116,7,8,9-tetrahydro-5-(3-hydroxypropyl)-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0174]

[0175] A solution of the product of Example 6 (3.0 g, 0.0155 mol) intetrahydrofuran (44 mL) under nitrogen was treated with a Borane.THFcomplex (1M, 18.56 mL) and this reaction was stirred for 2 hours.Methanol (2.50 mL) was added before a solution of saturated sodiumbicarbonate (2.32 mL) and hydrogen peroxide (30%, 2.32 mL) were addedresulting in a white precipitate. The precipitate was filtered off andthe solvent was removed from the filtrate under reduced pressure toafford the title compound.

[0176]¹H NMR (CDCl₃, 300 MHz) d 1.2-2.5 (m, 8H), 2.59 (m, 2H), 2.95 (dd,2H), 3.72 (m, 2H), 4.25 (m, 1H).

[0177]¹³C NMR (CDCl₃, 75 MHz) d 23.87, 25.73, 26.23, 28.57, 31.88,53.97, 61.90, 68.07, 159.9, 160.8.

EXAMPLE 125-(3-bromopropyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0178]

[0179] To a solution of the product of Example 11 in methylene chlorideat 0° C. is added carbon tetrabromide and triphenylphosphine. Thereaction is stirred for 2 hours and the solvent is removed under reducedpressure. The crude product is dissolved in an eluting solvent systemand chromatographed to afford the title compound.

EXAMPLE 13(E)-5-(2-butenyl)-6,7-dihydro-3H,5H,9H-[1,2,4]oxadiazolo[3,4-c][1,4]oxazepin-3-one

[0180]

[0181] Ex-13a) A solution of 55 g (550 mmol) of tetrahydropyran-4-one(Aldrich) and 50.4 mL (600 mmol) of pyrrolidine in benzene was stirredat reflux for three hours while collecting and removing the separatedwater in a Dean-Stark trap. This solution was allowed to cool to roomtemperature and was used without further purification in the followingstep.

[0182] Ex-13b) To the product solution from Example 13a was addeddropwise one equivalent of crotyl iodide in benzene. An exotherm to 55°C. was noted and a precipitate formed. The reaction was stirred for 18hours, diluted with 500 mL of water and stirred for an additional twohours. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic extracts were dried(MgSO₄), filtered and concentrated to afford a yellow oil. Distillation(60-80° C., 0.1 torr) of this material afforded 40.9 g (48%)of the2-(2-butenyl)tetrahydropyran-4-one as a colorless oil.

[0183] Ex-13c) The product of Example 13b (40.9 g, 266 mmol) wasdissolved in 150 mL of formic acid. To this solution was added 33.9 g(300 mmol) of hydroxylamine-O-sulfonic acid. This was stirred at refluxfor one hour. After cooling the reaction to room temperature it waspartitioned between water and methylene chloride. The organic layer wasseparated, dried (MgSO₄), filtered and concentrated to afford 27.1 g ofan oily solid. This material was purified via silica gel chromatographyeluting with 30% acetone/hexanes to yield 12.6 g (28% yield) of thelactam.

[0184] Ex-13d) The product of Example 13c (2 g, 10.6 mmol) was dissolvedin methylene chloride to which 1.57 g of trimethyloxoniumtetrafluoroborate was added. This mixture was stirred at roomtemperature for two days before it was diluted with aqueous sodiumbicarbonate. The separated organic layer was filtered through a pad ofsilica gel which was washed liberally with ethyl acetate. The combinedorganic eluant was dried (MgSO₄), filtered and concentrated to afford1.8 g (84%) of the iminoether.

[0185] Ex-13e) The product of Example 13d (1.8 g, 8.9 mmol) wasdissolved in 100 mL of ethanol to which 0.6 g (8.6 mmol) ofhydroxylamine hydrochloride was added. This reaction was stirred atreflux for twenty four hours. The solvent was then removed in vacuo toafford a tan solid. Crystallization of this crude material afforded 1.25g (66%) of the hydroxamidine as an amber solid.

[0186] Ex-13) The product of Example 13e (1.25 g, 6.8 mmol) wasdissolved in 25 mL of CH₂Cl₂ to which 1.1 g (7 mmol) of carbonyldiimidazole was added. This mixture was stirred overnight at roomtemperature. The reaction mixture was then washed with water, dried(MgSO₄), filtered and concentrated to afford 1 g of an oil. Purificationvia C-18 chromatography eluting with an 55% acetonitrile/water mixtureafforded 0.6 g (42%) of the desired title product.

[0187] Mass Spectra for C₁₀H₁₄N₂O₃: M⁺H=211.

[0188]¹H NMR (CDCl₃) d 1.8 (d, 3H), 2.4-2.6 (m, 2H), 2.8-3.1 (m, 2H),3.55 (m, 2H), 4.0 (m, 1H), 4.1 (m, 2H), 5.3 (m, 1H), 5.6 (m, 1H).

[0189]¹³C NMR (CDCl₃) 17.7, 29.0, 33.9, 56.4, 68.4, 72.2, 124.0, 130.1,158.0, 158.8.

[0190] Elemental analysis for C₁₀H₁₄N₂O₃+0.2 H₂O: Calcd. C, 56.17 H,6.79 N, 13.10 Found C, 56.45 H, 6.95 N, 12.84

EXAMPLE 149-ethyl-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0191]

[0192] Ex-14a) A sample of 3-ethylcaprolactam (5 g, 35.4 mmol) wasallowed to react with 6.8 g (46.0 mmol) of trimethyloxoniumtetrafluoroborate in 140 mL CH₂Cl₂ over a 5 day period. The productiminoether (4.7 g) was obtained as a pale yellow oil from the reactionmixture by the methods of Example 2f.

[0193] Ex-14b) The product of Example 14a (4.7 g, 30.3 mmol) was allowedto react with 2.19 g (30.3 mmol) of hydroxylamine hydrochloride in 40 mLMeOH for 24 hours. The hydroxamidine product was obtained as an oil bythe methods of Example 2g.

[0194] Ex-14) The product of Example 14b is allowed to react1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature andthe title compound is isolated from the reaction mixture using C₁₈reversed phase HPLC as described in Example 2.

EXAMPLE 155-(bromomethyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0195]

[0196] To a solution of the product of Example 5 in dichloromethane wasadded carbon tetrabromide (460 mg, 1.3 mmol). This solution was cooledin an ice bath and stirred for 5 minutes. Triphenylphosphine (437 mg,1.6 mmol) was added to the solution and stirring was continued for 5minutes at 0° C. before allowing it to warm slowly to room temperature.The solvent was removed under reduced pressure. The residue was placedon a filter and washed three times with ether. The filtrate solvent wasthen removed under reduced pressure to yield the title compound.

[0197] Mass Spectra for C₈H₁₁N₂O₂Br: M⁺H=246.

EXAMPLE 166,,7,8,9-tetrahydro-5-(2-nitroethyl)-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0198]

[0199] Ex-16a) The product of Example 2c (5.5 g; 30 mmol) was allowed toreact with trimethyloxonium tetrafluoroborate (5 g; 33 mmol) in 50 mL ofCH₂Cl₂. This mixture was stirred for 18 hours before saturated NaHCO₃(50 mL) was added. The mixture was stirred until gas evolution ceasedand the pH reached 8. The layers were separated and the organic phasewas dried over MgSO₄ and concentrated in vacuo to yield 5.8 g of theiminoether as an oil.

[0200] Ex-16b) The product of Example 16a was combined withhydroxylamine hydrochloride (4.2 g, 28 mmol) and ethanol (50 mL) andthen stirred at reflux for one hour. The mixture was cooled andconcentrated in vacuo. The residue was partitioned between saturatedNaHCO₃/CH₂Cl₂. The organic layer was dried over MgSO₄ and concentratedin vacuo to afford the hydroxamidine as an oil.

[0201] Ex-16) The product of Example 16b and 1,1′-carbonyldiimidazole(4.5 g; 0.028 mole) dissolved in 50 mL of CH₂Cl₂ were stirred 18 hours.The reaction mixture was washed with 10% KHSO₄ to remove excessimidazole. The organic solution was dried over MgSO₄ and concentrated invacuo. The residue was chromatographed on Merck silica, eluting with 40%EtOAc/hexane. The title compound eluted first off the column and wascrystallized upon concentration to yield 3.1 g of a white powder.

[0202] Mass spectra of C₉H₁₃N₃O₄: M⁺H=228.

[0203]¹H NMR (CDCl₃) d 1.4-1.6 (m, 1H); 1.75-1.86 (m, 2H); 1.95-2.19 (m,3H); 2.28-2.39 (m, 1H); 2.48-2.62 (m, 2H); 2.91-3.01 (ddt, 1H);4.28-4.38 (m, 1H); 4.38-4.54 (m, 2H).

EXAMPLE 174,5-dihydro-5-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-3-isoxazolecarboxylicacid

[0204]

[0205] Ex-17) A solution of 2.2 g (7 mmol) of the product of Example 10in 80 mL of acetone, 40 mL of water, and 20 mL of conc. HCl was stirredat reflux for three days. All solvent was removed in vacuo. The residue,dissolved in aqueous sodium bicarbonate, was washed with ethyl acetate,acidified with dilute HCl, and extracted with ethyl acetate. The organicextract was dried (MgSO₄), filtered and concentrated to afford 1 g (51%)of the title product as a colorless oil.

[0206]¹H NMR (CDCl₃) d 1.5 (bt, 1H), 1.8-2.2 (m, 7H), 2.5 (m, 1H),2.8-3.1 (m, 2H), 3.3-3.5 (m, 1H), 4.45 (m, 1H), 4.9 (m, 1H), 7.9 (bs,1H).

EXAMPLE 185-(3-butenyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0207]

[0208] EX-18a) A suspension of potassium t-butoxide in toluene cooled to0° C. in an ice bath under N₂ is treated with cyclohexanone. To thereaction mixture is slowly added 3-butenyl bromide. The reaction iswarmed to room temperature. The reaction is then poured into EtOAc andwashed once with 10% potassium hydrogen sulfate. The organic solution isthen washed with brine, dried over magnesium sulfate, and the solventevaporated under reduced pressure to afford 2-(3-butenyl) cyclohexanone.

[0209] EX-18b) A solution of the product of Example 18a in formic acidis stirred under N₂. To this solution is added hydroxylamine-O-sulfonicacid. The reaction is stirred at reflux, cooled to room temperature,stripped of solvent under reduced pressure. Ethyl acetate is poured intothe resulting black slurry and the mixture is neutralized with asolution of saturated sodium. The organic layer is separated, washedwith brine, dried over magnesium sulfate and stripped of solvent underreduced pressure to afford the lactam.

[0210] EX-18c) A solution of the product of Example 18b in CH₂Cl₂ isstirred under a blanket of N₂. To the solution is added trimethyloxoniumtetrafluoroborate. The reaction is refluxed while being monitored bythin layer chromatography and then cooled to room temperature. Thereaction is neutralized with a solution of saturated sodium bicarbonate.The organic layer is separated, washed with brine, and dried overmagnesium sulfate. The solvent is removed under reduced pressure toafford the iminoether.

[0211] EX-18d) To a solution of the product of Example 18c in methanolunder N₂ is added hydroxylamine hydrochloride. The reaction is broughtto reflux, cooled to room temperature, and stripped of all solvent underreduced pressure to afford the hydroxamidine.

[0212] EX-18) To a solution of the product of Example 18d in CH₂Cl₂under N₂ is added 1,1′-carbonyldiimidazole portion-wise. The reaction isthen stirred at room temperature. To the reaction is added a solution of10% potassium hydrogensulfate. The organic is separated, washed withbrine, dried over magnesium sulfate and stripped of all solvent underreduced pressure to afford the title compound.

EXAMPLE 19 6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-propanal

[0213]

[0214] To a solution of the product of Example 18 in dioxane and wateris added sodium periodate and osmium tetraoxide. The reaction is stirredat room temperature and monitored by thin layer chromatography. Water isadded to the reaction mixture and the solution is extracted with CH₂Cl₂.The organic layer is dried over magnesium sulfate, filtered, andstripped of all solvent under reduced pressure to afford the titlecompound.

EXAMPLE 205-(2-bromoethyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0215]

[0216] EX-20) The product of Example 9 (0.20 g, 0.01 mol) was treated bythe methods described in Example 12 to yield 0.21 g (81%) of the titlecompound.

[0217]¹H NMR (CDCl₃, 300 MHz) d 1.50-2.60 (m, 9H), 2.99 (dd, 1H), 3.35(m, 2H), 4.41 (m, 1H).

[0218]¹³C NMR (CDCl₃, 75 MHz) d 23.89, 25.33, 26.04, 28.06, 31.59,35.05, 52.79, 159.3, 160.2.

[0219] Elemental analysis for C₉H₁₃N₂O₂Br₁: Calcd. C, 41.40 H, 5.02N,10.73 Br, 30.60 Found C, 41.59 H, 5.07N, 10.60 Br, 30.86

EXAMPLE 21 bis(1,1-dimethylethyl)4-nitro-4-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]heptanedioate

[0220]

[0221] The product from example 16 (0.23 g, 1 mmole) was combined witht-butyl acrylate (0.26 g, 2 mmole) and K₂CO₃ in 5 mL of DMF. Thereaction mixture was stirred for 18 hours. The reaction mixture wasconcentrated and the residue was partitioned between CH₂Cl₂ and water.The organic layer was dried over MgSO₄ then concentrated. The residuecrystallized and was triturated with Et₂O to yield 354 mg of the titlematerial as a solid.

[0222] Elemental analysis for C₂₃H₃₇N₃O₈. Calc: C: 57.13 H: 7.75 N:8.69. Found: C: 57.24 H: 7.95 N: 8.53.

[0223] Mass Spectral analysis for C₂₃H₃₇N₃O₈: M⁺NH₄=501

[0224]¹H NMR (CDCl₃) d 1.38-1.58 (m, 18H); 1.6-2.0 (m, 5H); 2.1-2.4 (m,10H); 2.48-2.62 (m, 2H); 2.82-3.02 (m, 1H); 4.3-4.5 (m, 1H).

EXAMPLE 228,9-dihydro-5-[(phenylmethoxy)methyl]-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0225]

[0226] Ex-22a) The Boc protected nitrile was synthesized according tothe procedure published in J. Org. Chem. 56, 4196, 1991.

[0227]¹H NMR (CDCl₃) d 1.3-1.6 (m, 15H); 2.35-2.7 (m, 4H); 3.6-3.7 (dd,1H); 3.95-4.1 (t, 1H); 4.5-4.7 (m, 1H); 5.4-5.6 (m, 2H).

[0228] Ex-22b) The product of Example 22a (1.1 g, 3.9 mmol) wasdissolved in 25 mL of EtOH saturated with HCl at 0° C. This mixture wasallowed to warm to room temperature and stir for 18 hours. It was thenconcentrated in vavuo and the residue was triturated with ether toafford the ethyl imidate.

[0229]¹H NMR (DMSOd₆) d 1.3 (t, 3H); 2.3-2.9 (m, 4H); 3.4-3.6 (m, 2H);3.38-3.98 (m, 1H); 4.36-4.48 (m, 2H); 5.4-5.66 (m, 2H).

[0230] Ex-22c) Amberlyst A-27 (15.7 mL, 0.096 equivalents) was washedwith water, 2N NaOH, water, then EtOH. The product of Example 22b wasdissolved in EtOH and this solution was added to the Amberlyst A-27resin. This mixture was agitated for 18 hours. The mixture was thenfiltered and the resin washed with EtOH. The filtrate was concentratedand the residue purified by C-18 chromatography (0% to 30%CH₃CN/H₂O+0.05% TFA, 25 min.). The amidine eluted just after the solventfront. Removal of solvent in vacuo afforded the 450 mg of the amidine asan oil.

[0231]¹H NMR (MeODd₃) d 2.3-2.6 (m, 3H); 2.7-2.8 (m, 1H); 3.15-3.25 (m,1H); 3.55-3.8 (m, 2H); 5.4-5.6 (m, 1H); 5.75-5.9 (m, 1H).

[0232]¹³C NMR (MeODd₃) d 24.6, 28.3, 53.2, 63.0, 126.7, 130.3, 171.3

[0233] Elemental analysis for C₇H₁₂N₂O+1.1HCl+1.3MeOH: Calc: C, 44.92 H,8.31N, 12.62 Cl, 17.57 Found: C, 44.86 H, 7.84N, 12.24 Cl, 17.84

[0234] Ex-22d) The product of Example 22c is dissolved in pyridine andcooled to 0° C. The requisite amount of benzyl bromide is added and themixture is stirred until the tic indicates that the starting material isconsumed. The reaction mixture is concentrated and the residue ispartitioned between water and CH₂Cl₂. The organic phase is dried overMgSO₄ and concentrated to afford the benzyl ether.

[0235] Ex-22e) The product of Example 22d is dissolved in EtOHcontaining hydroxylamine and potassium t-butoxide. This solution isrefluxed until the starting material is consumed. The solvent is removedin vacuo. The residue is dissolved in water and made basic with K₂CO₃.The product is then extracted into CH₂Cl₂. The organic phase is driedover MgSO₄ and concentrated to afford the hydroxamidine.

[0236] Ex-22) The product of Example 22e is combined with1,1′-carbonyldiimidazolein CH₂Cl₂ and stirred until the thin layerchromatography (tlc) data indicates the starting material is consumed.The reaction mixture is washed with 10% KHSO₄ to remove excessimidazole. The organic solution is dried over MgSO₄ and concentrated invacuo. The residue is chromatographed on silica gel to afford the titlecompound.

EXAMPLE 23 5-ethyl-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-3-thione

[0237]

[0238] The product of Example 7b is allowed to react with1,1′-thiocarbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperatureand the title compound is isolated from the reaction mixture using C₁₈reverse phase HPLC as described in Example 2.

EXAMPLE 246-ethyl-7,8,9,10-tetrahydro-6H-[1,2,4]oxadiazino[4,3-a]azepine-3,4-dione

[0239]

[0240] The product of Example 7b is allowed to react with oxalylchloride in CH₂Cl₂ for 24 hours at room temperature and the titlecompound is isolated from the reaction mixture using C₁₈ reverse phaseHPLC as described in Example 2.

EXAMPLE 255-[(4-amino-1H-imidazol-2-yl)methyl]-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one,monohydrochloride

[0241]

[0242] Ex-25a) To a solution of the product of Example 8 in acetone isadded Jones reagent until the red color persists as described in J.Chem. Soc. 1956, 39. The reaction is then quenched with isopropylalcohol and concentrated under reduced pressure. The residue is thenpartitioned between brine and methylene chloride. The organic layer isback washed with a solution of sodium carbonate. The water layer is thenacidified with concentrated hydrochloric acid and the precipitate isfiltered and washed with water to afford the carboxylic acid.

[0243] Ex-25b) To a solution of the product of Example 25a in methylenechloride is added a catalytic amount of DMF. Oxalyl chloride is addeddropwise at room temperature and evolution of gas is observed. Thereaction is followed by thin layer chromatography to determine when thereaction is complete. The completed reaction is concentrated underreduced pressure and the residue is dissolved in methylene chloride. Thereaction mixture is cooled to 0° C. in an ice bath and ammonia isbubbled through it. The solvent is the removed under reduced pressureand the product is partitioned between brine and methylene chloride. Theorganic is dried over magnesium sulfate and solvent is removed underreduced pressure to afford the carboxamide.

[0244] Ex-25c) To a solution of the product of Example 25b in methylenechloride is added triethylamine. The reaction is cooled to 0° C. in anice bath and 12% phosgene in toluene is added dropwise. The reaction isstirred until completed as noted by thin layer chromatography. Thereaction is washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude residue ischromatographed to afford the nitrile.

[0245] Ex-25d) To a solution of ethanol saturated with hydrogen chlorideis added portion-wise the product of Example 25c. The reaction isallowed to warm to room temperature and is followed by thin layerchromatography. The completed reaction is concentrated and the residueis dissolved in ethanol to afford a solution of the ethyl acetimidate.

[0246] Ex-25) The product of Example 25d is allowed to react withaminoacetonitrile to give the title material.

EXAMPLE 26 4,5,5a,6,7,8,9,9a-octahydro-5-methyl-1-oxo-1H-[1,2,4]oxadiazolo[4,3-a]quinoline-8-propanoic acid

[0247]

[0248] Ex-26a) 7-bromo-4-methyl-quinolin-2-ol is prepared fromacetoacetic acid-(3-bromo-anilde) and sulfuric acid by the methoddescribed in Monti et. al.; Gazz. Chim. Ital; 66; 1936; 723.

[0249] Ex-26b) A solution of the product of Example 26a, Acrylic acidmethyl ester, tetrabutyl ammonium chloride, NaHCO₃, and Pd(OAc)₂ in DMFis heated at 85° C. for 16 h. The solvent is removed and the product ispurified by chromatography to afford the coupling product.

[0250] Ex-26c) A mixture of the product of Example 26b and platinumoxide in glacial acetic acid is hydrogented at room temperature and 50psi. The catalyst is filtered washed with acetic acid and concentrated.The desired lactam 26c is purified by column chromatography on silicagel.

[0251] Ex-26d) A portion of the product of Example 26c is allowed toreact with of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16hour period. The mixture is diluted with CH₂Cl₂ and washed with 5%NaHCO₃ and brine. The organic phase is dried over MgSO₄, filtered andthe solvent was evaporated in vacuo to afford the iminoether.

[0252] Ex-26e) The product of Example 26d is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0253] Ex-26f) The product of Example 26e is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Themethyl ester of the title compound is isolated from the reaction mixtureusing C₁₈ reverse phase HPLC.

[0254] Ex-26) The product of Example 26f is hydrolyzed in 10%hydrochloric acid at reflux followed by concentration under reducedpressure. The resulting crude product residue is dissolved in water andextracted with diethyl ether. The product is purified on an ion exchangeresin to produce the title material.

EXAMPLE 275,6,7,8-tetrahydro-5-(4-pentyl)-3H-[1,2,4]oxadiazolo[4,3-a]pyridin-3-one

[0255]

[0256] Ex-27a) Methyl 2-oxocyclopentanecarboxylate (4.2 g, 30 mmol),5-bromo-1-pentene (5.0 g, 33 mmol) and K₂CO₃, were combined in DMF (50mL) and stirred for 18 hours. The reaction mixture was then poured ontoice and the product was extracted two times with Et₂O then two timeswith hexane. The combined organic extracts were back washed with brine,dried over MgSO₄ and concentrated to yield approximately 4.0 g of the1-pentenyl, 1-methoxycarbonylcyclopentanone as an oil.

[0257]¹H NMR (CDCl₃) d 1.3-1.6 (m, 3H); 1.75-2.0 (m, 6H); 2.1-2.4( m,2H); 2.45-2.6 (m, 1H); 3.6-3.7 (m, 3H); 4.85-5.05 (m, 2H); 5.6-5.8 (m,1H).

[0258] Ex-27b) The product of Example 27a (0.42 g, 2 mmol) and LiCl(0.508 g, 12 mmol) were dissolved/suspended in 2.0 mL of DMF (DMF wasnot dried) and the mixture was placed in an oil bath heated to 153° C.The mixture was heated and stirred until gas evolution ceased. Thereaction mixture was cooled and diluted with an equal volume of water.The product was extracted into 1:1 Et₂O:hexane. The organic extractswere back washed with brine, dried over MgSO₄ and concentrated to yieldapproximately 300 mg of the pentenylcyclopentanone as an oil. Thismaterial was chromatographed eluting with 3% EtOAc/hexane to yield ananalytical sample.

[0259]¹H NMR (CDCl₃) d 1.2-1.35 (m, 1H); 1.36-1.6 (m, 3H); 1.65-1.8 (m,2H); 1.9-2.15 (m, 5H); 2.18-2.45 (m, 2H); 4.9-5.02 (m, 2H); 5.7-5.85 (m,1H).

[0260] Ex-27c) The product of Example 27b (0.3 g, 2 mmol) was combinedwith hydroxylamine hydrochloride (0.277 g, 4 mmol) and sodium acetate(0.41 g, 5 mmol) in EtOH (20 mL) and water (10 mL). This mixture wasrefluxed until tlc (20% EtOAc/hexane) indicated that the startingmaterial was consumed. The reaction mixture was concentrated to ⅓ of theoriginal volume and the product was extracted into 1:1 Et₂O:hexane. Theorganic extracts were back washed with brine, dried over MgSO₄ andconcentrated, to yield approximately 223 mg of an oil. The oil waschromatographed on silica eluting with EtOAc/hexane to yield 155 mg ofthe oxime as an oil.

[0261]¹H NMR (CDCl₃) d 1.28-1.5 (m, 3H); 1.54-1.9 (m, 4H); 1.65-1.8 (m,2H); 1.95-2.1 (m, 2H); 2.26-2.64 (m, 2H); 4.88-5.02 (m, 2H); 5.7-5.86(m, 1H); 8.75 (s, 1 H).

[0262]¹³C NMR (CDCl₃) d 22.2, 27, 27.5, 31.89, 31.92, 34.2, 42.5, 116,138.5, 168.

[0263] Ex-27d) TMSPPE was prepared by combining P₂O₅ (20 g, 146 mmol)and Hexamethyldisiloxane (49.6 mL, 234 mmol) in toluene (200 mL) andrefluxed until the mixture was homogeneous. This mixture was cooled toroom temperature and the product of Example 27c (9.5 g, 58 mmol) wasadded. This mixture was stirred and after 6 hours the mixture started todevelop a red color which became deeper with time. A tlc in 100% CH₃CNafter 18 & 20 hours indicated a trace of starting material, but that thereaction had not changed. An equal volume of water was added and themixture stirred for 2 hours. The phases were separated and the aqueousphase was washed with CH₂Cl₂. The combined organic extracts were backwashed with brine, dried over MgSO₄ and concentrated, to yield 9.2 g ofa mixture of the regioisomers of the lactam as an oil. A 4.0 g sample ofthis oil was chromatographed (silica gel) eluting with 100% CH₃CN, toyield 1.4 g of the desired 7-isomer.

[0264] 1H NMR (CDCl₃) d 1.3-1.52 (m, 5H); 1.56-1.72 (m, 1H); 1.8-1.94(m, 2H); 2.0-2.1 (q, 2H); 2.18-2.42 (m, 2H); 3.28-3.4 (m, 1H); 4.92-5.02(m, 2H); 5.68-5.82 (m, 1H); 6.9 (s, 1H).

[0265] Ex-27) The product of Example 27d (1.42 g; 8.5 mmol) was reactedby the methods described in Example 16 to yield 0.8 g of the titlecompound as an oil.

[0266] Mass Spectra for C₁₁H₁₆N₂O₂: M⁺H=209.

[0267]¹H NMR (CDCl₃) d 1.35-1.48 (m, 2H); 1.49-1.68 (m, 1H); 1.7-1.95(m, 4H); 1.95-2.39 (m, 3H); 2.6-2.75 (m, 2H); 3.8-3.9 (m, 1H); 4.89-5.03(m, 2H); 5.66-5.82 (m, 1H).

EXAMPLE 285,6,7,8-tetrahydro-3-oxo-3H-[1,2,4]oxadiazolo[4,3-a]pyridine-5-butanal

[0268]

[0269] Ex-28) The product of Example 27 (0.42 g; 2 mmol) and NaIO₄ (0.86g; 4 mmol) were dissolved in a mixture of 12 mL of dioxane and 8 mL ofH₂O. Two drops of a 2% solution of OsO₄ in n-butanol was added to themixture. The reaction mixture was stirred until tlc (100% EtOAc)indicated that the starting material was consumed. A precipitate hadformed and was filtered. This solid was washed with dioxane. Thefiltrate was concentrated and the residue was partitioned betweenH₂O/CH₂Cl₂. The organic layer was dried over MgSO₄ and concentrated toafford the title compound as an oil.

[0270]¹H NMR (CDCl₃) d 1.4-2.2 (m, 7H); 2.3-2.7 (m, 4H); 3.7-3.9 (m,2H); 9.7 (s, 1H).

EXAMPLE 296,7-dihydro-5-pentyl-3H,5H-pyrrolo[2,1-c][1,2,4]thiadiazole-3-thione

[0271]

[0272] Ex-29a) A suspension of ethyl acrylate, 1-nitrohexane, K₂CO₃, andAliquat 336 (6 drops) is sonicated for 5 h. To the reaction is addedEt₂O. The reaction mixture is filtered, extracted with brine, dried overNa₂SO₄ (anhydrous), filtered, and concentrated under reduced pressure togive a yellow liquid. The product is purified by column chromatographyto give methyl 4-nitrononanoate.

[0273] Ex-29b) The product of Example 29a is reduced under catalytichydrogenation conditions in methanol (60 psi, 55° C.) using Raneynickel. The reaction is heated for 8 h to effect cyclization afterreduction of the nitro group. After concentrating the reaction mixtureunder reduced pressure, the residue is purified by column chromatographyto give 5-n-pentyl-pyrrolidine-2-one.

[0274] Ex-29c) This lactam product of Example 29b is treated withtrimethyloxonium tetrafluoroborate as described in Example 2f to givethe corresponding imino ether.

[0275] Ex-29d) The imino ether product of Example 29c and hydroxylaminehydrochloride are refluxed in methanol under a nitrogen atmosphere for3.5 h. After cooling the reaction to room temperature, it is filtered,stripped of all solvent under reduced pressure, and partitioned betweenwater and EtOAc. The organic and aqueous phases are separated and theaqueous phase is washed with another portion of EtOAc before it islyophilized to provide 5-n-pentyl-2-hydroximinopyrrolidinehydrochloride.

[0276] Ex-29) The product of Example 29d is treated with carbondisulfidein an alcoholic KOH solution by the procedure of Chem. Ber. 22, 2441(1889) to give the title material.

EXAMPLE 30 5,6,7,8-tetrahydro-5-propyl[1,2,3,5]oxathiadiazolo[3,4-a]pyridine 3,3-dioxide

[0277]

[0278] Ex-30a) Cyclopentanone is treated with potassium-t-butoxide andthen with allyl bromide in the same manner and in the same proportionsas described for cyclohexanone in Example 6a, yielding2-allylcyclopentanone.

[0279] Ex-30b) A sample of the 2-allylcyclopentanone product of Example30a is combined with NH₂OH.HCl and sodium acetate in a mixture ofethanol and water. This mixture is refluxed for 5 h under a nitrogenatmosphere and stirred at room temperature for an additional 5 days. Allsolvent is removed under reduced pressure. The residue is partitionedbetween ethyl acetate and water and the organic phase is washed with1×75 mL of saturated NaCl (brine), dried over Na₂SO₄, and stripped ofall solvent under reduced pressure, giving the corresponding oxime.

[0280] Ex-30c) A sample of the oxime product of Example 30b is added toa dropping funnel containing 80% H₂SO₄. After using a stirring rod toobtain a turbid solution, this mixture is added dropwise (10 min) to 80%H₂SO₄ stirred magnetically and maintained at 120° C. with an externaloil bath. An exotherm may be noted and the temperature of the reactionmay rise to 160° C. before cooling again to 120° C. Ten minutes laterthe flask is removed from the bath and allowed to cool to roomtemperature. The product mixture is diluted with water and brought to pH6 with concentrated NH₄OH. This solution is further diluted with ofwater and extracted with 3 portions of CH₂Cl₂. The combined organicphase is washed with 1×50 mL of brine, dried (Na₂SO₄), filtered, andstripped of all solvent under reduced pressure to give the lactam.Silica column chromatography is used to separate the 3-allylpiperidine-2-one from the desired 6-allyl piperidine-2-one.

[0281] Ex-30d) The 6-allyl-piperidine-2-one product of Example 30c isreduced with palladium on carbon in methanol under hydrogen to give the6-n-propyl-piperidine-2-one.

[0282] Ex-30e) The 6-n-propyl-piperidine-2-one product of Example 30d istreated with trimethyloxonium tetrafluoroborate as described in Example2f to give the corresponding imino ether.

[0283] Ex-30f) The imino ether product of Example 30e is treated with ofhydroxylamine hydrochloride as described in Example 2g to give thecorresponding hydroxyamidine.

[0284] Ex-30g) The hydroxyamidine product of Example 30f is allowed toreact with 1,1′-sulfonyldiimidazole in CH₂Cl₂ for 24 hours at roomtemperature. The title compound is isolated from the reaction mixtureusing C₁₈ reversed phase HPLC (water-acetonitrile gradient).

EXAMPLE 31 6,7-dihydro-5-pentyl-3H-pyrrolo[1,2-a]imidazole-2,3(5H)-dione

[0285]

[0286] Ex-31a) A suspension of ethyl acrylate, 1-nitrohexane, K₂CO₃, andAliquat 336 (6 drops) is sonicated for 5 h. To the reaction is addedEt₂O. The reaction mixture is filtered, extracted with brine, dried overNa₂SO₄ (anhydrous), filtered, and concentrated under reduced pressure togive a yellow liquid. The product is purified by column chromatographyto give methyl 4-nitrononanoate.

[0287] Ex-31b) The product of Example 31a is reduced under catalytichydrogenation conditions in methanol (60 psi, 55 C) using Raney nickel.The reaction is heated for 8 h to effect cyclization after reduction ofthe nitro group. After concentration of the reaction mixture underreduced pressure, the residue is purified by column chromatography togive 5-n-pentyl-pyrrolidine-2-one.

[0288] Ex-31c) This lactam product of Example 31b is treated withtrimethyloxonium tetrafluoroborate as described in Example 2f to givethe corresponding imino ether.

[0289] Ex-31d) The imino ether product of Example 31c and ammoniumchloride (NH₄Cl) are refluxed in methanol under a nitrogen atmospherefor 3.5 h. After cooling the reaction to room temperature, it isfiltered, stripped of all solvent under reduced pressure, andpartitioned between water and EtOAc. The organic and aqueous phases areseparated and the aqueous phase is washed with another portion of EtOAcbefore it is lyophilized to provide 5-n-pentyl-2-iminopyrrolidinehydrochloride.

[0290] Ex-31) The product of Example 31d is treated with oxalyl chlorideand diazabicyclooctane in acetonitrile to give the title compound, whichis purified by partition between water and EtOAc, and passage over asilica column.

EXAMPLE 32

[0291] 5,6,7,8-tetrahydro-7-methyl-5-propyl-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-2-one

[0292] Ex-32a) Methyl Propionate is deprotonated with lithiumdiisopropylamide in THF at −30° C. and treated with1-bromo-2-oxopentane. The product methyl 2-methyl-4-oxohepatoate isisolated by partition of the reaction mixture between water andmethylene chloride.

[0293] Ex-32b) The product methyl ester of Example 32a is hydrolyzedwith lithium hydroxide in methanol to provide the free acid.

[0294] Ex-32c) The resulting free acid of Example 32b is reduced to thecorresponding alcohol by careful addition of borane in THF, giving2-methyl-4-oxo-1-heptanol.

[0295] Ex-32d) Treatment of the product alcohol of Example 32c withmethanesulfonyl chloride in pyridine gives the corresponding mesylate.

[0296] Ex-32e) The mesylate product of Example 32d is treated withpotassium cyanide in DMSO to give 3-methyl-5-oxo-ocanenitrile.

[0297] Ex-32f) The 3-methyl-5-oxo-ocanenitrile product of Example 32e isreduced to the corresponding alcohol with aluminum isopropoxide inisopropanol.

[0298] Ex-32g) This 6-methyl-7-cyano-4-heptanol product of Example 32fis treated with carbon tetrabromide and triphenylphosphine to give3-methyl-5-bromo-ocanenitrile.

[0299] Ex-32h) The 3-methyl-5-bromo-ocanenitrile product of Example 32gis reacted with hydroxylamine hydrochloride to give1-hydroxy-4-methyl-6-n-propyl-2-iminopiperidine.

[0300] Ex-32) The product of Example 32h is condensed withcarbonyldiimidazole to give the title compound.

EXAMPLE 337,8-dihyro-7-methyl-6-(2-propenyl)-3H-pyrrolo[1,2-b][1,2,4]oxadiazine-2,3(6H)-dione

[0301]

[0302] Ex-33a) Diethylketone is deprotonated with lithiumdiisopropylamide in THF at −30° C. and treated with bromoacetonitrile.The product is isolated by partition of the reaction mixture betweenwater and methylene chloride. The organic layer is dried and stripped ofall solvent to yield the 3-methyl, 4-oxovaleronitrile product.

[0303] Ex-33b) The product methyl ester of Example 33a is reduced to thecorresponding alcohol with aluminum isopropoxide in isopropanol.

[0304] Ex-33c) The product of Example 33b is treated with carbontetrabromide and triphenylphosphine to give 3-methyl,4-bromovaleronitrile

[0305] Ex-33d) The product of Example 33c is reacted with hydroxylaminehydrochloride to give 1-hydroxy-4-methyl-5-ethyl-2-iminopyrrolidine.

[0306] Ex-33) The product of Example 33d is allowed to react with oxalylchloride in pyridine to give the title material.

EXAMPLE 34 Methyl5,6,7,8-tetrahydro-6,8-dimethyl-3-oxo-7-(trifluoromethyl)-3H-[1,2,4]oxadiazolo[4,3-a]pyridine-5-acetate

[0307]

EXAMPLE 355-(3-butenyl)-6,7,8,9-tetrahydro-5H-[1,2,3,5]oxathiadiazolo[3,4-a]azepine3-oxide

[0308]

[0309] Ex-35a) The reactions with cyclohexanone described in Examples6a-6d are repeated with the replacement of allyl bromide by3-butenyl-1-bromide to generate the hydroxyamidine hydrochloride.

[0310] Ex-35) The hydroxyamidine hydrochloride product of Example 35a istreated at 0° C. with thionyl chloride in acetonitrile in the presenceof triethylamine. The reaction mixture is poured on ice and extractedwith three portions of methylene chloride. The organic fractions arecombined, dried, flitered, stripped, and purified by silicachromatography to give the title compound.

EXAMPLE 36

[0311] 6,7-dihydro-5-pentyl-3H,5H-pyrrolo[2,1-c][1,2,4]thiadiazol-3-one

[0312] Ex-36a) As depicted in Scheme 10, 2-Trimethylsilylethanol istreated with tosyl chloride in pyridine to give2-trimethylsilyl-1-tosylethane.

[0313] Ex-36b) The product of Example 36a is treated with sodiumhydrosulfide to give 2-trimethylsilylethanethiol.

[0314] Ex-36c) The 2-trimethylsilylethanethiol hydrochloride product ofExample 35a is treated with chloramine to give1-thia-3-trimethylsilyl-n-propylamine hydrochloride.

[0315] Ex-36d) The imino ether product from Example 31 is treated with2-thia-3-trimethylsilyl-n-propylamine hydrochloride in refluxingmethanol to give compound 36d.

[0316] Ex-36) The product of Example 36d is treated under anhydrousconditions with anhydrous tetrabutylammonium flouride, followed bycarbonyldiimidazole, to give the title compound.

EXAMPLE 375-(ethoxymethyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0317]

[0318] Ex-37a) A sample of the product of Example 5 (1.3 g, 7.2 mmol)and carbontetrabromide (3.0 g, 8.9 mmol) in CH₂Cl₂ (70 mL) was cooled to0° C. To this stirred mixture was added triphenylphosphine (2.8 g, 10.7mmol) portion-wise. The reaction was allowed to warm to room temperatureand stirr for 18 h. After the reaction was concentrated, the residue wasdissolved in a minimum of 20% acetonitrile/toluene and chromatographedon silica eluting with the dissolving solvent mixture to produce 1.5 g(86%) of the bromomethyl intermediate.

[0319] Ex-37) To the product of Example 37a or the product of Example 15in ethanol is added an ethanolic solution of sodium ethoxide. After thinlayer chromatography indicates the reaction is complete, it isconcentrated and the residue partitioned between water and an extractionsolvent. The dried organic layer is stripped of all solvent and theresidue chromatographed to produce the title material.

EXAMPLE 385-[(ethylthio)methyl]-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0320]

[0321] The product of Example 37a or the product of Example 15 isreacted with sodium thioethoxide by the methods of Example 37 togenerate the title material.

EXAMPLE 395-[(ethylsulfinyl)methyl]-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0322]

[0323] The product of Example 38 is reacted with one equivalent of MCPBAin CH₂Cl₂ to generate the title material.

EXAMPLE 405-[(ethylsulfonyl)methyl]-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0324]

[0325] To the product of Example 38 in MeOH is added excess 30% H₂O₂ andthe solution warmed sufficiently to generate the title material.

EXAMPLE 416,7,8,9-tetrahydro-5-(1-oxo-3-butenyl)-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-3-one

[0326]

[0327] Ex-41a) A sample of the product of Example 4 (0.5 g, 2.0 mmol)dissolved in 5 mL of THF was treated with 2.5 mL of water that 0.23 g(85% pellets, 4.1 mmol) of potassium hydroxide had dissolved in. Afterstirring this reaction for 45 min, it was poured into a mixture ofEtOAc(50 mL) and 1M KHSO₄. The organic layer was separated, dried, andconcentrated to produce the crude carboxylic acid intermediate product.This material can be used crude or purified by chromatography.

[0328] Ex-41b) To a sample of the product of Example 41a dissolved inDMF is added O,N-dimethylhydroxylamine hydrochloride,1(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride,1-hydroxybenzotriazole hydrate, and triethyl amine. The reaction mixtureis stirred overnight at room temperature to yield the methoxymethylamide after purification.

[0329] Ex-41) A solution of the product of Example 41b in THF is cooledand subsequently treated with a THF solution of allylmagnesium bromide.The reaction is warmed to room temperature and worked up. The titlematerial is isolated by chromatography.

EXAMPLE 42N-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl]ethyl]methanesulfonamide

[0330]

[0331] The product of Example 3 dissolved in an organic solvent isreacted with excess triethyl amine followed by excess methyl sulfonylchloride to yield the title material following work up andchromatography.

EXAMPLE 435-(2-aminomethyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo-[4,3-a]azepin-3-one

[0332]

[0333] Ex-43a) The product of Example 15 (1.55 g, 6.27 mmol) wasdissolved in 15 mL of dimethylformamide (DMF), and then sodium azide(2.04 g, 31 mmol) was added to this solution. The resulting mixture wasstirred under nitrogen at 50° C. overnight, at which time HPLC analysisindicated that the bromomethyl starting material had disappeared. TheDMF was removed under reduced pressure. The residue was dissolved inethyl acetate and water. The EtOAc layer was washed with water, 0.1 NHCl, water and brine, dried over Na₂SO₄, filtered and evaporated to give1.26 g (96%) of the desired azide product as a yellow oil (95% pure byHPLC analysis). ¹H NMR (CDCl₃) d 4.53 (m, 1H), 3.61 (m, 2H), 2.96 (m,1H), 2.57 (m, 1H), 2.18 (m, 1H), 2.07 (m, 1H), 1.95 (m, 1H), 1.76 (m,2H), 1.55 (m, 1H). MS C₈H₁₁N₅O₂ m/z=210.2 [M+H]⁺.

[0334] The azide product from Ex-43a (180 mg, 0.86 mmol) was dissolvedin 10 mL of THF and 0.4% water, then polymer-bound PPh₃ (320 mg, 0.94mmol; loaded with 3 mmol PPh₃/g) was added. The resulting mixture wasstirred under nitrogen at room temperature overnight, at which time massspectral analysis indicated that the azide starting material haddisappeared and a new signal corresponding to the desired amine producthad formed. The polymer was removed by filtration and was washed withmethanol. The filtrate was evaporated to give 100 mg of the desired5-(2-aminomethyl)-6,7,8,9-tetrahydro-3H,5H-[1,2,4]oxadiazolo-[4,3-a]azepin-3-oneproduct as an off-white solid. ¹H NMR (CDCl₃) d 4.24 (m, 1H), 3.29 (m,2H), 2.86 (m, 1H), 2.10 (m, 2H), 1.88 (m, 2H), 1.77 (m, 2H), 1.48 (m,1H). HRMS calcd. for C₈H₁₃N₃O₂: 184.1086 [M+H]⁺; found 184.1067.

EXAMPLE 44

[0335]N-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo-[4,3-a]azepin-5-yl]methyl]methanesulfonamide

[0336] The product of Example 43 dissolved in an organic solvent isreacted with excess triethylamine followed by excess methyl sulfonylchloride to yield the title material following work up andchromatography.

[0337] Additional Examples 45-51 can be prepared by one skilled in theart using similar methods, as shown in Example 44.

EXAMPLES 45-51

[0338]

Ex. No. R_(SUB1) 45 phenyl 46 4-MeO₂C—C₆H₄— 47 3-MeO₂C—C₆H₄— 482-MeO₂C—C₆H₄— 49 2-MeO₂C-3-thienyl- 50 5-MeO₂C-2-furyl- 51 MeO₂C—CH₂CH₂—

EXAMPLE 52N-Methyl-N-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]-oxadiazolo-[4,3-a]azepin-5-yl]methyl]methanesulfonamide

[0339]

[0340] The product of Example 44 dissolved in an organic solvent isreacted with excess diazomethane in diethyl ether at 0-5° C. overnightto yield the title material following work up and chromatography.

[0341] Additional Examples 53-59 can be prepared by one skilled in theart using similar methods.

EXAMPLES 53-59N-Methyl-N-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl]methyl]sulfonamides.

[0342]

Ex. No. R_(SUB1) 53 phenyl 54 4-MeO₂C—C₆H₄— 55 3-MeO₂C—C₆H₄— 562-MeO₂C—C₆H₄— 57 2-MeO₂C-3-thienyl- 58 5-MeO₂C-2-furyl- 59 MeO₂C—CH₂CH₂—

EXAMPLE 60

[0343]

[0344] The product of Example 43 dissolved in an organic solvent isreacted with excess methyl glycidate to yield the indicated materialfollowing work up and chromatography.

EXAMPLE 61

[0345]

[0346] The product of Example 15 (247 mg, 1 mmol) was dissolved in 5 mLof DMF. Potassium carbonate (138 mg, 1 mmol) and methyl amine (0.5 mL, 2M in THF) were added, and the resulting mixture was stirred undernitrogen at room temperature overnight, at which time HPLC analysisindicated that the bromomethyl starting material disappeared. The DMFwas removed under reduced pressure. The residue was partitioned betweenmethylene chloride and water, the aqueous layer was extracted withmethylene chloride. The combined organic layers were concentrated, andthe resultant crude product was purified by reverse phase HPLC to give30 mg (18%) of the desired olefinic product as an off-white oil. ¹H NMR(CDCl₃) d 5.34 (dd, 2H), 2.70 (m, 2H), 2.40 (m, 2H), 1.84 (m, 2H). ¹³CNMR (CDCl₃) d 159.17 (CO), 157.61 (CO), 138.47(C═), 114.46(C═), 35.39(CH₂), 29.72 (CH₂), 26.27 (CH₂), 24.85 (CH₂). ¹³C NMR DEPT (CDCl₃) 35.39(CH₂), 29.72 (CH₂), 26.27 (CH₂), 24.85 (CH₂). MS C₈H₁₀N₂O₂ m/z=167.2[M+H]⁺.

EXAMPLE 62

[0347]

[0348] Ex-62a) To a DMF (15 mL) solution of the bromide product fromExample 15 (1.50 g, 6.1 mmol) was added potassium thioacetate (1.32g,11.6 mmol). The resulting cloudy brown solution was stirred at roomtemperature for 18 hours. The reaction mixture was poured into brine andthe organic layer was separated. The organic layer was washed with waterand brine, dried (MgSO₄) and evaporated to give 1.48 g (100%) of thedesired thioacetate product as a tan solid. LCMS: m/z=265.0 [M+Na]. ¹HNMR (CDCl₃) d 1.47 (m, 1H), 1.7-2.0 (m, 3H), 2.13 (m, 1H), 2.32 (s, 3H),2.74 (m, 1H), 2.97 (m, 1H), 3.03 (dd, 1H), 3.42 (dd, 1H), 4.33 (m, 1H).

[0349] The thioacetate product from Ex-62a (1.48 g, 6.1 mmol) wasdissolved in 10% EtOH in CHCl₃ (50 mL) and cooled in an ice/water bath.Chlorine gas was bubbled through the stirred solution until a yellowcolor persisted (approximately 5 minutes). The resulting slurry wasstirred for 90 minutes in an ice bath. The solvent was removed undervacuum to give 1.58 g (96%) of the desired sulfonyl chloride product asa white solid. LCMS: m/z=267.0 [M+H]⁺. ¹H NMR (10% d₆DMSO in CDCl₃) d1.21 (q, 1H), 1.5-1.7 (m, 3H), 1.85 (m, 1H), 2.02 (m, 1H), 2.33 (m, 1H),2.65 (dd, 1H), 2.96 (m, 2H), 4.53 (m, 1H).

EXAMPLE 63

[0350]

[0351] The product of Example 62 dissolved in an organic solvent isreacted with excess triethylamine followed by excess proline methylester hydrochloride to yield the indicated proline sulfonamide followingwork up and chromatography.

[0352] Additional Examples 64-77 can be prepared by one skilled in theart using similar methods.

EXAMPLES 64-77[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl]methyl]sulfonamides.

[0353]

Ex. No. R_(SUB1) 64 MeO₂C—CH₂CH₂— 65 3-MeO₂C—C₆H₄— 66 2-MeO₂C—C₆H₄— 672-MeO₂C-3-thienyl- 68 MeO₂C—CH(CH₃)— 69 MeO₂C—CH(CH₂OH)— 70MeO₂C—CH₂CH(CH₃)— 71 MeO₂C—CH(CH₃)CH₂— 72 MeO₂C—CH₂— 73 (EtO)₂PO—CH₂CH₂—74 (EtO)₂PO—CH₂— 75 MeO₂C—CH(OH)CH₂— 76 H 77 MeOSO₂—CH₂CH₂—

EXAMPLE 78

[0354]

[0355] The product of Example 72 dissolved in an organic solvent isreacted with excess diazomethane in diethyl ether at 0-5° C. overnightto yield the indicated N-methylsulfonamide material following work upand chromatography.

[0356] Additional Examples 79-90 can be prepared by one skilled in theart using similar methods.

EXAMPLES 79-90N-Methyl-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl]methyl]sulfonamides.

[0357]

Ex. No. R_(SUB1) 79 MeO₂C—CH₂CH₂— 80 3-MeO₂C—C₆H₄— 81 2-MeO₂C—C₆H₄— 822-MeO₂C-3-thienyl- 83 MeO₂C—CH(CH₃)— 84 MeO₂C—CH(CH₂OH)— 85MeO₂C—CH₂CH(CH₃)— 86 MeO₂C—CH(CH₃)CH₂— 87 MeOSO₂—CH₂CH₂— 88(EtO)₂PO—CH₂CH₂— 89 (EtO)₂PO—CH₂— 90 MeO₂C—CH(OH)CH₂—

EXAMPLE 91

[0358]

[0359] The product of Example 62 dissolved in an organic solvent isreacted with excess triethylamine followed by excess methylisonipecotate to yield the indicated piperidine sulfonamide followingwork up and chromatography.

EXAMPLE 92

[0360]

[0361] The product of Example 15 dissolved in an organic solvent isreacted with excess aqueous sodium carbonate followed by excess4-methoxycarbonyl phenylboronic acid and a catalytic amount oftetrakistriphenylphosphine palladium to yield the indicatedp-substituted benzoate ester following work up and chromatography.

EXAMPLE 93

[0362]

[0363] The product of Example 15 dissolved in an organic solvent isreacted with excess triethylamine followed by excess diethylmercaptomethyl phosphonate to yield the indicated phosphonomethylthioether product following work up and chromatography.

EXAMPLE 94

[0364]

[0365] The product of Example 15 dissolved in an organic solvent isreacted with excess triethylamine followed by excess 1,2,4-triazole toyield the indicated N-substituted triazole product following work up andchromatography.

EXAMPLE 95

[0366]

EXAMPLE 96

[0367]

[0368] A sample of the product of Example (5) (4.2 g, 22.5 mmol)dissolved in a mixture of 27 mL of pyridine and 50 mL of CH₂Cl₂ wascooled to 0° C. To this was added dropwise 1.9 mL (25.1 mmol) of methanesulfonyl chloride. The reaction was allowed to slowly warm to roomtemperature and stirr over night before all solvent was removed underreduced pressure. Toluene (10 mL) was added to the residue and again allsolvent was removed under reduced pressure. The residue was diluted witha mixture of EtOAc (200 mL) and 1M KHSO₄ (50 mL). The organic layer wasseparated, washed with brine, dried (MgSO₄), and concentrated to produce4.1 g of the title product. This material can be used crude or purifiedby chromatography.

[0369] Elemental analysis for C₉H₁₄N₂O₅Cl: Calcd: C, 41.21 H, 5.98 N,10.68. Found: C, 41.29 H, 5.93 N, 10.45.

EXAMPLE 97

[0370]

[0371] Argon was bubbled through a solution of n-butanol (0.07 g, 0.76mmol) dissolved in 10 mL of THF. To this stirred solution was added a60% dispersion of sodium hydride(33.6 mg, 0.84 mmol). After gasevolution had ceased, a sample of the product of Example (96) (0.2 g,0.76 mmol) dissolved in 5 mL of THF was added to the stirred reactionmixture. The reaction was allowed to stirr for 6 hours before it waspoured into a mixture of EtOAc and 1M KHSO₄. The organic layer wasseparated, dried, and concentrated to produce 120 mg of crude titleproduct. This material was purified by chromatography to yield 70 mg ofthe title product.

EXAMPLE 98

[0372]

[0373] Argon was bubbled through a solution of Garner's alcohol (0.88 g,3.81 mmol) dissolved in 40 mL of THF. To this stirred solution was addeda 60% dispersion of sodium hydride. After gas evolution had ceased, asample of the product of Example (96) (1.0 g, 3.81 mmol) dissolved in 5mL of THF was added to the stirred reaction mixture. The reaction wasallowed to reflux for 2 hours before it was cooled to room temperatureand worked up as described by Example (97). This material was purifiedby chromatography to yield 830 mg of the title product.

EXAMPLE 996,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-carboxylicacid

[0374]

[0375] Potassium hydroxide (0.47 g, 8.39 mmol) was dissolved in 10 mL of50% aqueous THF. To this was added a solution of the product of Example4 in 6 mL THF and the reaction mixture was stirred for 2 h at 25° C.Diethylether (20 mL) was then added and the reaction mixture was madeacidic by adding 10 mL of 1N HCl. The organic layer was separated, driedover magnesium sulfate, filtered and all solvent evaporated to give 0.43g (52% yield) of the title product. The structure of the compound wascharacterized by ¹H and ¹³C NMR.

EXAMPLE 1006,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-carboxylicacid chloride

[0376]

[0377] To a solution of the 5 g of the product of Example (99) in 50 mLCH₂Cl₂ was added thionyl chloride (50 mL) and the reaction mixture wasstirred for 6 h at 20° C. The solvent was evaporated under reducedpressure to give 5.1 g of the white title product residue which wascharacterized by ¹H NMR.

EXAMPLE 1016,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-methoxymethycarboxylicacid amide

[0378]

[0379] To a solution of the product of Example (99) (5 g, 21.01 mmol) inmethylene chloride (45 mL) was added carbonyl diimidazole (CDI, 3.71 g,23.11 mmol) and the reaction mixture was stirred for 10 min.Methoxymethyl amine (2.25 g, 23.11 mmol) was then added to the abovereaction mixture and stirring was continued for 16 h at 25° C. A 1Npotassium hydrogen sulfate solution (50 mL) was then added before thissolution was extracted with 200 mL of toluene. The organic layer waswashed with saturated aq. sodium bicarbonate and then brine, dried overmagnesium sulfate, filtered and evaporated to give 4.59 g (91% yield) ofthe title product.

EXAMPLE 102

[0380]

EXAMPLE 103

[0381]

EXAMPLE 104

[0382]

EXAMPLE 105

[0383]

EXAMPLE 106

[0384]

EXAMPLE 107

[0385]

EXAMPLE 108

[0386]

EXAMPLE 109

[0387]

EXAMPLE 110

[0388]

[0389] EX-110 To a solution of EX-20 (5.71 g, 0.026 mol) in toluene (25mL) was added triphenylphosphine (7.17 g,0.027 mol). The reaction washeated at reflux in an oil bath for 16 hours. After cooling, the toluenewas decanted from the glassy solid. The solid was triturated withdiethyl ether overnight to afford the title product (10.21 g, 0.020 mol)in 90% yield.

[0390]¹H NMR (CDCl₃, 300 MHz) d 1.50-2.9(m, 11H), d 3.58 (m, 1H), d4.16(m, 1H), d 4.41(m, 1H) d 7.6-8.0(m, 15H).

[0391]¹³C NMR (CDCl₃, 75 MHz) d 24.43, 24.97, 25.50, 55.08, 55.27,116.9, 118.1, 130.4, 130.6, 133.5, 135.1, 135.2, 159.4, 160.

[0392]³¹P NMR (CDCl₃, 300 MHz) d 26.0.

EXAMPLE 111

[0393]

[0394] Ex-111 To a 50 mL 3-neck round bottom flask fitted with anaddition funnel was added EX-110 (5.0 g, 0.010 mol) in THF(20 mL). Thesolution was cooled to −78° C. in a dry ice bath. To the solution wasadded potassium bis(trimethylsilyl)amide (0.5M)(21 mL, 0.021 mol) slowlyso that the temperature would not raise above −72° C. The reactionstirred at −78° C. for 15 minutes. The dry-ice bath was placed so thatthe reaction stirred at −45° C. for 1.5 hours. To the reaction was addedGamer's Aldehyde (1.97 g, 0.009 mol) drop wise so that the temperaturedid not raise above −72° C. The reaction stirred for an additional 45minutes then the dry ice bath was removed and stirred at roomtemperature for 4 hours. To the reaction was added a saturated solutionof ammonium chloride. The organics were collected and washed withbrine(3×25 mL), dried over magnesium sulfate anhydrous, removed underreduced pressure. The product was purified utilizing flashchromatography with 30:70 ethyl acetate:hexane to afford the title (1.85g, 0.005) compound in 54.7% yield.

[0395]¹H NMR (CDCl₃, 300 MHz) d 1.21(s, 9H), d 1.25-3.0 (m,.15H), d3.65(dd, 1H), d 4.11 (m, 1H), d 5.40(m, 4H).

[0396] Mass Spec m/z 394.5(M+H), m/z 432.4(M+K), m/z 294.4(M+H−100).

EXAMPLE 112

[0397]

[0398] Ex-112 To a 2N hydrochloric acid dissolved in methanol (20 mL)solution was added Ex-111 (1.13 g, 0.003 mol). The reaction stirred for3 hours. The solvent was removed in vacuo to afford the title product inquantitative yield.

[0399] Mass Spec: 254.1(M+H).

EXAMPLE 113

[0400]

[0401] Ex-113 To a flask was added Ex-15 (1 g, 0.004 mol) andtriphenylphosphine (1.08 g, 4.1 mol). The mixture was placed into an oilbath which held a constant temperature of 110° C. for 16 hours. When thereaction cooled, the glassy solid was triturated with diethyl ether for10 hours. The title product was isolated as a fine white powder (0.93 g,0.002 mol) in 50% yield.

[0402]³¹P NMR (CDCl₃, 300 MHz) d 22(s).

[0403] Chemical Analysis: C₂₆H₂₆N₂O₂BrP carbon hydrogen nitrogen brominecalculated 61.31 5.14 5.50 15.69 found 58.64 5.19 5.64 17.46

EXAMPLE 114

[0404]

[0405] EX-114 The procedure to make EX-110 was followed to afford thetitle product in 98% yield.

[0406]¹H NMR (CDCl₃, 300 MHz) d1.38-2.61(m, 9H), d 2.85 (dd, 1H), d3.60(m, 1H), d 3.19(m, 1H), d 4.45(m, 1H), d 7.60-7.9(m, 15H).

EXAMPLE 115

[0407]

[0408] Ex-115 To a 50 mL 3-neck round bottom flask fitted with anaddition funnel was added EX-114 (5.0 g, 0.010 mol) in THF (20 mL). Thesolution was cooled to −78° C. in a dry ice bath. To the solution wasadded potassium bis(trimethylsilyl)amide (0.5M)(21 mL, 0.021 mol) slowlyso that the temperature would not raise above −72° C. The reactionstirred at −78° C. for 15 minutes. The dry-ice bath was placed so thatthe reaction stirred at −45° C. for 1.5 hours. To the reaction was addedGarner's Aldehyde (1.97 g, 0.009 mol) drop wise so that the temperaturedid not raise above −72° C. The reaction stirred for an additional 45minutes then the dry ice bath was removed and stirred at roomtemperature for 4 hours. To the reaction was added a saturated solutionof ammonium chloride. The organics were collected and washed withbrine(3×25 mL), dried over magnesium sulfate anhydrous, removed underreduced pressure. The product was purified utilizing flashchromatography with 30:70 ethyl acetate:hexane to afford the title(1.85g, 0.005) compound in 40% yield.

[0409]¹H NMR (CDCl₃, 300 MHz) d 1.21(s, 9H), d 1.25-3.0 (m,17H), d3.65(dd, 1H), d 4.11(m, 2H), d 4.2(t, 1H), d 4.6(d, 1H), d 5.40(m, 2H).

[0410] Mass Spec m/z 408.2(M+H).

EXAMPLE 116

[0411]

[0412] Ex-116 To a 2N hydrochloric acid dissolved in methanol(20 mL)solution was added Ex-115 (1.13 g, 0.003 mol). The reaction stirred for3 hours. The solvent was removed in vacuo to afford the title product inquantitative yield. ¹H NMR (D₂O, 300 MHz) d 1.21(t, 1H), d 1.45(q, 1H),d 1.6-2.3 (m,9H), d 2.50 (t,1H), d 3.35(dd, 1H), d 3.49(m, 1H), d 3.7(m,2H), d 4.21(t, 1H), d 5.40(m, 2H). Mass Spec m/z 268.1(M+H).

EXAMPLE 117

[0413]

[0414] EX-117 A solution of BH₃ (1M)(26 mL) in THF was cooled to 0° C.in an ice bath. To this solution was added a solution Ex-27 (5.0 g,0.025 mol) in dry THF (25 mL) drop wise via an addition funnel. Thereaction stirred at 0° C. for 2.5 hours. To the reaction was added a 3%hydrogen peroxide at a pH of 10, adjusted IN sodium hydroxide. After 3hours, ethyl acetate(50 mL) was added and was partitioned betweenbrine(50 mL). The organics were collected and dried over magnesiumsulfate anhydrous then removed under reduced pressure. The pale yellowoil was purified by flash chromatography using 1:1 ethyl acetate:hexaneto afford the title product (2.42 g) in 30% yield.

[0415]¹H NMR (CDCl₃, 300 MHz) d1.4-2.2(m, 15H), d 2.51 (t, 1H), d2.89(dd, 1H), d 3.61(q, 2H), d 4.25(m, 1H).

EXAMPLE 118

[0416]

[0417] EX-118 A solution of 8 mL (16 mmol) 2 M oxalylchloride in CH₂Cl₂was diluted with 15 mL CH₂Cl₂. It was cooled to −60° C. and 5 mL (70mmol) DMSO was added very slowly. After 5 minutes stirring 2.1 g (11.4mmol) alcohol in 50 mL CH₂Cl₂ was added and the mixture was stirred for30 minutes at −60° C. To this mixture was added 10 mL (72 mmol) TEA andstirring continued for 16 hours. The mixture was diluted with 200 mLCH₂Cl₂ and washed with 2×100 mL sat. KHSO₄ and brine. The organic phasewas dried over MgSO₄ and the solvent was evaporated in vacuo, yielding 2g (96%) of the title product as oil.

[0418] FAB MS: MH⁺=183.0

EXAMPLE 119

[0419]

[0420] EX-119A The nitro-lactam (5.5 g; 0.03 mole) was combined withtrimethyloxonium tetrafluoroborate (5.0 g; 0.033 mole) anddissolved/suspended in 50 ml of CH₂Cl₂. The mixture was stirred for 18hours, where the mixture was homogenous. Saturated NaHCO₃ (50 ml) wasadded and the mixture stirred until gas evolution ceased and the pH wasat least 8. The layers were separated and the organic phase was driedover MgSO₄ and concentrated in vacuo, yielding 5.8 g of an oil.

[0421] EX-119B The above oil was combined with hydroxylaminehydrochloride (4.2 g; 0.028 mole) and ethanol (50 ml) then refluxed forone hour. The mixture was cooled and concentrated in vacuo. The residuewas partitioned between saturated NaHCO₃/CH₂Cl₂. The organic layer wasdried over MgSO₄ and concentrated in vacuo, yielding an oil.

[0422] EX-119 This oil was combined with 1,1′-carbonyldiimidazole (4.5g; 0.028 mole) and dissolved in 50 ml of CH₂Cl₂, and stirred 18 hours.The reaction mixture was washed with 10% KHSO₄ to remove excessimidazole. The organic solution was dried over MgSO₄ and concentrated invacuo. The residue was chromatographed on Merck silica, eluting with 40%EtOAc/hexane. The desired product eluted first off the column andcrystallized upon concentration, to yield 3.1 g of a white powder.

[0423] C₉H₁₃N₃O₄, MW 227.218.

[0424] Mass Spec: M+H@228

[0425]¹H NMR (CDCl₃) * 1.4 to1.6, m (1H); 1.75 to 1.86, m (2H); 1.95 to2.19, m (3H); 2.28 to 2.39, m (1H); 2.48 to 2.62, m (2H); 2.91 to 2.98 &2.98 to 3.01, d of d of t (1H); 4.28 to 4.38, m (1H); 4.38 to 4.54, m(2H).

EXAMPLE 120 EXAMPLE 121

[0426]

[0427] EX-120/121 The product of EX-119 (1.0 g) was separated into thetwo enantiomers on a reverse phase chiral column. The first componentwas EX-120 (459 mg) and the second component was EX-121 (429 mg).

EXAMPLE 122

[0428]

[0429] EX-122a Methyl 2-oxocyclopentanecarboxylate (4.2 g; 0.03 mole),5-bromo-1-pentene (5.0 g; 0.033 mole) and K₂CO₃, were combined in DMF(50 ml) and stirred 18 hours. The reaction mixture was poured on to iceand the product was extracted two times with Et₂O then two times withhexane. The combined organic extracts were back washed with brine, driedover MgSO₄ and concentrated, to yield approximately 4.0 g of an oil.

[0430]¹H NMR (CDCl₃) * 1.3 to1.6, m (3H); 1.75 to 2.05, m (6H); 2.1 to2.4, m (2H); 2.45 to 2.6, m (1H); 3.6 to 3.7, m (3H); 4.85 to 5.05, m(2H); 5.6 to 5.8, m (1H).

[0431] EX-122b The crude product (420 mg; 0.002 mole) and LiCl (508 mg;0.012 mole) were dissolved/suspended in 2.0 ml of DMF (DMF was notdried) and the mixture was placed in an oil bath heated to 153° C. Themixture was heated and stirred until gas evolution ceased. The reactionmixture was cooled and diluted with an equal volume of water. Theproduct was extracted into 1:1 Et₂O:hexane. The organic extracts wereback washed with brine, dried over MgSO₄ and concentrated, to yieldapproximately 300 mg of an oil. Tlc 20% EtOAc/hexane indicated that thestarting material was consumed.

[0432] EX-122c Chromatography of 247 g eluting with 3% EtOAc/hexaneyielded 102 g of the desired product.

[0433]¹H NMR (CDCl₃) * 1.2 to1.35, m (1H); 1.36 to 1.6, m 3H); 1.65 to1.8, m (2H); 1.9 to 2.15, m (5H); 2.18 to 2.45, m (2H); 4.9 to 5.02, m(2H); 5.7 to 5.85, m (1H).

[0434] EX-122d The olefinic ketone (300 mg; 0.002 mole) was combinedwith hydroxylamine hydrochloride (277 mg; 0.004 mole) and sodium acetate(410 mg; 0.005 mole) in EtOH (20 ml) and water (10 ml). This wasrefluxed until tlc 20% EtOAc/hexane indicated that the starting materialwas consumed. The reaction mixture was concentrated to ⅓ of the originalvolume and the product was extracted into 1:1 Et₂O:hexane. The organicextracts were back washed with brine, dried over MgSO₄ and concentrated,to yield approximately 223 mg of an oil. The oil was chromatographed onsilica, eluting with EtOAc/hexane, yielding 155 mg of an oil.

[0435]¹H NMR (CDCl₃) * 1.28 to1.5, m (3H); 1.54 to 1.9, m (4H); 1.65 to1.8, m (2H); 1.95 to 2.1, m (2H); 2.26 to 2.64, m (2H); 4.88 to 5.02, m(2H); 5.7 to 5.86, m (1H); 8.75, s (1 H).

[0436]¹³C NMR (CDCl₃) * 22.2, 27, 27.5, 31.89, 31.92, 34.2, 42.5, 116,138.5, 168.

[0437] EX-122E TMSPPE was prepared by combining P₂O₅ (20 g, 0.146 mole)and Hexamethyldisiloxane (49.6 ml, 0.234 mole) in toluene (200 ml) andrefluxed until the mixture was homogeneous. This mixture was cooled toroom temperature and the oxime (9.5 g, 0.058 mole) was added. Thismixture was stirred, and after 6 hours the mixture started to develop ared color, which-became deeper with time. Tlc 100% CH₃CN after 18 & 20hours indicated a trace of starting material, but that the reaction hadnot changed. An equal volume of water was added and the mixture stirredfor 2 hours. The phases were separated and the aqueous phase was washedwith CH₂Cl₂. The combined organic extracts were back washed with brine,dried over MgSO₄ and concentrated, to yield 9.2 g of an oil containingboth regio isomers. 4.0 g of the oil was chromatographed, eluting with100% CH₃CN, to yield 1.4 g of the desired regio isomer.

[0438]¹H NMR (CDCl₃) * 1.3 to1.52, m (5H); 1.56 to 1.72, m (1H); 1.8 to1.94, m (2H); 2.0 to 2.1, q (2H); 2.18 to 2.42, m (2H); 3.28 to 3.4, m(1 H); 4.92 to 5.02, m (2H); 5.68 to 5.82, m (1H); 6.9, s (1H).

[0439] EX-122 The olefinlactam (1.42 g; 0.0085 mole) was carried on asdescribed in Example 119 to yield 770 mg of an oil.

[0440] C₁₁H₁₆N₂O₂, MW 208.25.

[0441] Mass Spec: M+H@208.9

[0442]¹H NMR (CDCl₃) * 1.35 to1.48, m (2H); 1.49 to 1.68, m (1H); 1.7 to1.95, m (4H); 1.95 to 2.39, m (3H); 2.6 to 2.75, m (2H); 3.8 to 3.9, m(1H); 4.89 to 5.03, m (2H); 5.66 to 5.82, m (1H).

EXAMPLE 123 EXAMPLE 124

[0443]

[0444] EX-123/124 The product from Example 119 (227 mg; 0.001 mole) wascombined with acrylonitrile (106 mg; 0.002 moles) and potassiumcarbonate (149 mg; 0.001 moles) in DMF (5.0 ml). The reaction mixturewas stirred under nitrogen for 48 hr. The starting material wasconsumed. The reaction mixture was concentrated and the residue waspartitioned between H₂O/CH₂Cl₂. The organic layer was dried over MgSO₄then concentrated. The residue was chromatographed by prep tlc. Elutedwith 40% EtOAc/hexane. Two products were collected:

[0445] The less polar component (30 mg) was EX-123.

[0446] C₁₂H₁₅N₃O₃, MW 280.28.

[0447] Mass Spec: M+H@281.

[0448] Elemental Analysis: Calc: C: 51.42 H: 5.75 N: 19.99 Found: C:51.16 H: 5.72 N: 19.87.

[0449] The more polar component (107 mg) was EX-124.

[0450] C₁₂H₁₅N₃O₃, MW 249.27.

[0451] Mass Spec: M+H@250.

[0452]¹H NMR (CDCl₃) * 1.1 to2.95, m (11H); 3.5, s (2H); 4.2 to 4.8, m(2H).

EXAMPLE 125(2S,3Z)-2-amino-5-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-3-pentenoicacid

[0453]

[0454] Ex-125a) A suspension of potassium t-butoxide (200 g, 1.78 mol)in toluene which was cooled to 0° C. in an ice bath under N₂ was treatedwith cyclohexanone (157 g, 1.60 mol). To the reaction mixture was slowlyadded allyl bromide (194 g, 1.60 mol) over a 2 hour period. The reactionwarmed to room temperature over 5 hours. The reaction was then pouredonto ethyl acetate (400 mL) and washed once with 10% potassium hydrogensulfate (250 mL). The organic solution was then washed with brine (3×200mL), dried over magnesium sulfate, and evaporated under reducedpressure. The resulting oil was then chromatographed to yield the allylcyclohexanone as an oil, 158.4 g (71.6%).

[0455]¹H NMR (CDCl₃, 300 MHz) d 1.2-2.5(m, 10H), 2.59 (m, 1H), 5.0(dd,2H), 5.75(m, 1H).

[0456]¹³C NMR (CDCl₃, 75 MHz) d 25.04, 28.03, 33.46, 33.86, 42.12,50.35, 116.3, 136.6, 212.5.

[0457] Ex-125b) A solution of the product of Ex-125a (56.4 g, 0.408 mol)in formic acid (200 mL) stirred under N₂ for 5 minutes. To this solutionwas added hydroxylamine-O-sulfonic acid (97%, 53.0 g, 0.448 mol). Thereaction was refluxed for 45 minutes then the solvent was removed underreduced pressure. Ethyl acetate was poured onto the resulting blackslurry and neutralized with a solution of saturated sodium bicarbonateuntil the evolution of gas ceased. The organic was separated, washedwith brine (3×150 mL), dried over magnesium sulfate anhydrous andremoved under reduced pressure. The resulting dark brown solid waschromatographed with 1:1 ethyl acetate:hexane to afford the caprolactamas a cream colored solid, 18.5 g (30%).

[0458]¹H NMR (CDCl₃, 300 MHz) d1.25(m, 2H), 1.42(m, 2H), 1.86(m, 2H),2.15(m, 2H), 2.33(m, 2H), 3.28(m, 2H), 5.04(dd, 2H), 5.64(m, 1H)6.07(bs, 1H).

[0459]¹³C NMR (CDCl₃, 75 MHz) d 23.30, 29.87, 35.51, 37.14, 40.66,53.05, 118.9, 134.1, 177.9.

[0460] Ex-125c) A solution of the product of Ex-125b (10 g, 0.068 mol)in methylene chloride (200 mL) stirred under a blanket of N₂ for 5minutes. To the solution was added Meerwein's reagent (13.09 g, 0.089mol) in two portions which had been ground into a powder. The reactionwas stirred for 16 hours while being monitored by thin layerchromatograph. The reaction was neutralized by a solution of saturatedsodium bicarbonate until the evolution of gas ceased and the pH was 10.The organic was separated, washed with brine (3×100 mL), dried overmagnesium sulfate anhydrous, then removed under reduced pressure. Theimino ether was isolated as an oil (˜10 g) and carried to the nextreaction with no further purification.

[0461] Ex-125d) To a solution of the product of Ex-125c (˜10) inmethanol (100 mL) under N₂ was added hydroxylamine hydrochloride (5.92g, 0.085 mol). The reaction refluxed for 2 hours then was cooled to roomtemperature. The solvent was removed under reduced pressure thenmethylene chloride (100 mL) and water (100 mL) was added to theresulting oil. To the well stirred bilayer was added K₂CO₃ until the pHof the water was 10.5. The organics were then separated, washed withbrine (3×100 mL), dried over magnesium sulfate anhydrous and removed invacuo. The hydroxamidine was isolated as a cream colored solid (˜11 g)and was carried on without further purification.

[0462] Ex-125e) To a round bottom flask was added the product of Ex-125d(˜11 g) in methylene chloride (150 mL) under N₂. To a separate roundbottom flask was added 1,1′-carbonyldiimidazole (CDI) (12.15 g, 0.079mol) in methylene chloride. Both flasks were cooled to 0° C. in an icebath. To the flask containing the CDI was added the solution of theproduct of example 1d via a canula. After the last of the addition, thereaction stirred in the ice bath as it warmed to room temperatureovernight. To the reaction was added a solution of 10% potassiumhydrogensulfate (200 mL). The organic was separated, washed with brine(3×100 mL), dried over magnesium sulfate anhydrous, then removed underreduced pressure. The resulting solid was chromatographed with 1:1 ethylacetate:hexane to afford the oxadiazolinone, 8.02 g (60.6%).

[0463]¹H NMR (CDCl₃, 300 MHz) d1.50-2.25(m, 6H), 2.51 (m, 4H), 2.87 (dd,2H), 4.29(m, 1H), 5.05(dd, 2H), 5.75(m, 1H).

[0464]¹³C NMR (CDCl₃, 75 MHz) d 23.97, 25.66, 26.32, 31.22, 36.52,53.45, 119.1, 133.0, 159.7, 160.7.

[0465] Ex-125f) A solution of the product of Ex-125e (3.0 g, 0.015 mol)in methylene chloride and methanol(75/45 mL) was cooled to −78° C. in adry ice bath. The reaction stirred as ozone was bubble through, thesolution at a 3 ml/min flow rate. When the solution stayed a consistentdeep blue, the ozone was remove and the reaction was purged withnitrogen. To the cold solution was added sodium borohydride(2.14 g,0.061 mol) very slowly to minimize the evolution of gas at one time. Tothe reaction was added glacial acetic acid slowly to bring the pH to 3.The reaction was then neutralized with saturated sodium bicarbonate. Theoraganics were then washed 3×50 mL with brine, dried over magnesiumsulfate anhydrous, removed under reduced pressure. The pale oil was runthrough a plug of silica (15 g) to afford the hydoxyethyl product, 5.15g, 0.026 mol (64%).

[0466]¹H NMR (CDCl₃, 300 MHz) d 1.18-2.15 (m, 8H), 3.59 (m, 2H), 4.39(m, 1H).

[0467]¹³C NMR (CDCl₃, 75 MHz) d 24.45, 25.71, 26.47, 32.56, 34.67,51.16, 58.85, 160.66, 160.89.

[0468] Ex-125g) In a solution of the product of Ex-125f (5.15 g, 0.026mol) in methylene chloride(100 mL) at 0° C. in an ice bath was addedcarbon tetrabromide (10.78 g, 0.033 mol). The solution was cooled to 0°C. in an ice bath. Then triphenylphosphine (10.23 g, 0.39 mol) was addedportion-wise as not to allow the temperature raise above 3° C. Thereaction was stirred for 2 hours and the solvent was removed in vacuo.The crude was purified by flash chromatography to yield the bromoethylproduct, 5.9 g, 0.023 mol (87%).

[0469]¹H NMR (CDCl₃, 300 MHz) d 1.50-2.60(m, 9H), 2.99 (dd, 1H), 3.35(m,2H), 4.41(m, 1H).

[0470]¹³C NMR (CDCl₃, 75 MHz) d 23.89, 25.33, 26.04, 28.06, 31.59,35.05, 52.79, 159.3, 160.2.

[0471] Elemental analysis for C₁₁H₁₆N₂O₃: carbon hydrogen nitrogenbromine calculated 41.40 5.02 10.73 30.60 found 41.59 5.07 10.60 30.86

[0472] Ex-125h) To a solution of the product of Ex-125g (5.71 g, 0.026mol) in toluene (25 mL) was added triphenylphosphine (7.17 g, 0.027mol). The reaction was stirred at reflux in an oil bath for 16 hours.After cooling, the toluene was decanted from the glassy solid. The solidwas tritrated with diethyl ether overnight to afford the phosphoniumbromide (10.21 g, 0.020 mol) in 90% yeild.

[0473]¹H NMR (CDCl₃, 300 MHz) d 1.50-2.9(m, 11H), d 3.58 (m, 1H), d4.16(m, 1H), d 4.41(m, 1H) d 7.6-8.0(m, 15H).

[0474]¹³C NMR (CDCl₃, 75 MHz) d 24.43, 24.97, 25.50, 55.08, 55.27,116.9, 118.1, 130.4, 130.6, 133.5, 135.1, 135.2, 159.4, 160.

[0475]³¹P NMR (CDCl₃, 300 MHz) d 26.0.

[0476] Ex-125i) To a 50 mL 3-neck round bottom flask fitted with anaddition funnel was added the product of Ex-125i (5.0 g, 0.010 mol) in20 mL of THF. The solution was cooled to −78° C. in a dry ice bath. Tothe solution was added potassium bis(trimethylsilyl)amide (0.5M)(21 mL,0.021 mol) slowly so that the temperature would not raise above −72° C.The reaction stirred at −78° C. for 15 minutes. To the reaction wasadded Garner's Aldehyde (1.97 g, 0.009 mol) drop wise so that thetemperature did not raise above −72° C. The reaction stirred for anadditional 45 minutes then the dry ice bath was removed and stirred atroom temperature for 4 hours. To the reaction was added a saturatedsolution of ammonium chloride. The organics were collected and washedwith brine(3×25 mL), dried over magnesium sulfate anhydrous, removedunder reduced pressure. The product was purified utilizing flashchromatography with 30:70 ethyl acetate:hexane to afford the protectedamino alcohol (1.85 g, 0.005) in 54.7% yield.

[0477]¹H NMR (CDCl₃, 300 MHz) d 1.21(s, 9H), d 1.25-3.0 (m,.15H), d3.65(dd, 1H), d 4.11(m, 1H), d 5.40(m, 4H).

[0478] Mass Spec m/z 394.5(M+H), m/z 432.4(M+K), m/z 294.4(M+H−100).

[0479] Ex-125j) To a solution of the product of Ex-125i (1.13 g, 0.003mol) in methylene chloride(20 mL) was added triflouroacetic acid(4 mL).The reaction stirred for two hours then a solution of 5% potassiumcarbonate was added. The organics were collected and washed withbrine(3×20 mL), dried over magnesium sulfate anhydrous, removed underreduced pressure. To the resulting residue was added acetone(20 mL). Tothis solution was added Jone's Reagent(8N, 20 drops). After 2 hours, thereaction was monitored by TLC and starting material remained. Twentyadditional drops were pipetted in and the reaction stirred over night.To the reaction was added methanol(10 mL). To the slurry was added water(100 mL) and the reaction was purified by reverse phase chromatographyto afford the title product.

[0480]¹H NMR (D₂O, 300 MHz) d 1.0-2.5 (m,.7H), d 3.5(d, 1H), d 4.6(d,1H), d 5.35(t, 1H), d 5.75(m, 1H).

[0481] Mass Spec: 226.3(M+H).

EXAMPLE 126a-amino-4,5,5a,6,7,8,9,9a-octahydro-5-methyl-1-oxo-1H-[1,2,4]oxadiazolo[4,3-a]quinoline-8-propanoic acid

[0482]

[0483] Ex-126a) 7-bromo-4-methyl-quinolin-2-ol is prepared fromacetoacetic acid-(3-bromo-anilde) and sulfuric acid by the methoddescribed in Monti et. al.; Gazz. Chim. Ital; 66; 1936; 723.

[0484] Ex-126b) N-Butoxycarbonyldehydroalanine methyl ester is preparedby the method of Gladisli et. al.; Tetrahedron Asymmetry; 2; 7; 1991;623-632. A solution of the product of Ex.-126a,N-butoxycarbonyldehydroalanine methyl ester, tetrabutyl ammoniumchloride, NaHCO₃, and Pd(OAc)₂ in DMF is heated at 85° C. for 16 h. Thesolvent is removed and the product is purified by chromatography toafford the coupling product.

[0485] Ex-126c) A mixture of the product of Ex.-126b and platinum oxidein glacial acetic acid is hydrogented at room temperature and 50 psi.The catalyst is filtered washed with acetic acid and concentrated. Thedesired lactam 126c is purified by column chromatography on silica gel.

[0486] Ex-126d) A portion of the product of Ex-126c is allowed to reactwith of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16 hourperiod. The mixture is diluted with CH₂Cl₂ and washed with 5% NaHCO₃ andbrine. The organic phase is dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0487] Ex-126e) The product of Ex-126d is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0488] Ex-126f) The product of Ex-126e is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Thetitle compound is isolated from the reaction mixture using C₁₈ reversephase HPLC.

[0489] Ex-126g) The product of Ex-126f is hydrolyzed in 10% hydrochloricacid at reflux followed by concentration under reduced pressure. Theresulting crude product residue is dissolved in water and extracted withdiethyl ether. The product is purified on an ion exchange resin toproduce the title material.

EXAMPLE 127N-[(1,1-dimethylethoxy)carbonyl]-3-[[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]amino]-L-alanine

[0490]

[0491] Ex-127a) A solution of 2 g (10 mmol) of the product of Ex-125fwas allowed to react with 2.04 g (10 mmol) N-a-Boc-L-diaminopropionicacid in 30 mL DMF (containing 0.3 mL acetic acid) with stirring for 1hour. To this solution was added 1.25 g (20 mmol) NaCNBH₃ and stirringwas continued for 18 hours. The DMF was evaporated in vacuo and theresidue was dissolved in 200 mL ethyl acetate. The organic solution waswashed with 2×100 mL 10% KHSO₄ and brine. The organic phase was driedover MgSO₄, filtered and the solvent was evaporated in vacuo, yielding1.7 g (44%) of the title product as a slightly yellow oil.

[0492] Mass spectral analysis for C₁₇H₂₈N₄O₆: M+H=385.

EXAMPLE 128N-[(1,1-dimethylethoxy)carbonyl]-3-[ethyl[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]amino]-L-alanine

[0493]

[0494] Ex-128) A solution of 1.7 g (4.4 mmol) of the product of Ex-127was dissolved in 30 mL DMF (containing 0.3 mL acetic acid) and 0.22 mL(5 mmol) acetaldehyde. This was stirred vigorously for 30 minutes. Tothis mixture was then added 0.625 g (10 mmol) NaCNBH₃ and stirring wascontinued for 18 hours. The DMF was evaporated in vacuo and the residuewas dissolved in 100 mL ethyl acetate. This organic solution was washedwith 2×50 mL 10% KHSO₄ and brine. The organic phase was dried overMgSO₄, filtered and the solvent was evaporated in vacuo to afford 1.4 g(77%) of the title product as a yellow oil.

[0495] Mass spectral analysis for C₁₉H₃₂N₄O₆: M+H=412.

EXAMPLE 129 phenylmethyl(2S,4Z)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-pentenoate

[0496]

[0497] Ex 129a) To a flask was added the product of Ex-131j (1 g, 0.004mol) and triphenylphosphine (1.08 g, 4.1 mol). The mixture was placedinto an oil bath which held a constant temperature of 110° C. for 16hours. When the reaction cooled, the glassy solid was tritrated withdiethyl ether for 10 hours. The phosphonium bromide was isolated as afine white powder (0.93 g, 0.002 mol) in 50% yield.

[0498]³¹P NMR (CDCl₃, 300 MHz) d 22(s).

[0499] Chemical Analysis: C₂₆H₂₆N₂O₂BrP carbon hydrogen nitrogen brominecalculated 61.31 5.14 5.50 15.69 found 58.64 5.19 5.64 17.46

[0500] Ex-129b) A solution of BH₃ (1M)(900 mL) in THF was cooled to 0°C. in an ice bath. To this solution was added a solution ofBoc-Asp-OBn(150 g, 0.464 mol) in dry THF (300 mL) drop wise via anaddition funnel. The reaction stirred at 0° C. for 2.5 hours. To thereaction was added a 5% glacial acetic acid:methanol solution slowly.After 20 minutes the solvents were removed in vacuo and the residue waspartitioned between ethyl acetate and 1N hydrochloric acid. The aqueouslayer was back washed with ethyl acetate (1×). The combined organicswere washed with brine(2×) then with saturated sodium bicarbonate, driedover magnesium sulfate anhydrous and removed under reduced pressure. Thepale yellow oil was purified by running it through a plug of silica (650g) to afford the aspartic alcohol (106 g) in 74% yield.

[0501] Ex-129c) The product of Ex-129b (10.05 g, 0.033 mol) was thencombined with 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC)(26.65g, 0.139 mol) and DMSO(10 mL) in methylene chloride(125 mL). A streamover nitrogen was passed over the solution and exhausted into a bleachsolution. The reaction was cooled in an ice bath. To the reaction, aslurry at this point, was added dichloroacetic acid(4.19 g, 0.033 mol)slowly. After ½ hour the ECD dissolved and the ice bath was removed. Thereaction stirred over night. To the reaction was added DI water(50 mL)and methylene chloride(50 mL). The organics were collected and washedwith brine (3×50 mL), dried over magnesium sulfate anhydrous, thenremoved under reduced pressure. The product was purified using flashchromatography with 1:1 ethyl acetate:hexanes to afford the asparticaldehyde (7.5 g, 0.024 mol) in 75% yield.

[0502] Mass Spec: m/z308.4(M+H), m/z314.4(M+Li), m/z264.3(M—CO₂),m/z208.3(M-Boc).

[0503] Ex-129d) To a 50 mL 3-neck round bottom flask fitted with anaddition funnel is added the product of example 5a in 20 mL of THF. Thesolution is cooled to −78° C. in a dry ice bath. To this solution isadded potassium bis(trimethylsilyl)amide (0.5M) slowly so that thetemperature does not raise above −72° C. The reaction is stirred at −78°C. for 15 minutes. To the reaction is added the product of example 5cdropwise so that the temperature does not raise above −72° C. Thereaction is stirred for an additional 45 minutes then the dry ice bathis removed and is stirred at room temperature for 4 hours. To thereaction is added a saturated solution of ammonium chloride. Theorganics are collected and washed with brine(3×25 mL), dried overmagnesium sulfate anhydrous, removed under reduced pressure. The productis purified utilizing flash chromatography with 30:70 ethylacetate:hexane to afford the title product.

EXAMPLE 130a-amino-5-fluoro-6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-hexanoicacid

[0504]

EXAMPLE 131N-[(1,1-dimethylethoxy)carbonyl]-S-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-L-cysteine

[0505]

[0506] Ex-131a) Anhydrous HCl was bubbled into a mixture of 25 g (0.14moles) of 2-aminopimellic acid in 500 ml of MeOH until the solid wasdissolved. After standing for 18 hours, the reaction was concentrated toafford 33.5 g (100%) of the bis-methyl ester as a white solid HCl salt.The HCl salt product was neutralized by addition of a small amount ofwater containing 1 equivalent of sodium bicarbonate. The aqueous mixturewas extracted with EtOAc and the organic extract was dried (MgSO₄),filtered and concentrated to afford 22 g of the amino-pimelate.

[0507] Ex-131b) A solution of 17 g (0.084 moles) of the product ofEx-131a in 900 ml of p-cymene was stirred at reflux for two days. Allsolvent was removed in vacuo and the residue was recrystallized fromcyclohexane to afford 12.2 g (85%) of 7-(methoxycarbonyl)caprolactam asan off-white solid.

[0508]¹H NMR (CDCl₃, 300 MHz) d 1.5-2.5 (m, 8H), 3.7 (s, 3H), 4.0 (m,1H), 6.4 (s, 1H).

[0509] Melting Point (Mettler FP900) 79.5-85.8° C.

[0510] Ex-131c) To a solution of the product of Ex-131b (70.01 g, 0.409moles) in dichloromethane (500 ml) was added Trimethyloxoniumtetrafluoroborate(75.68 g, 0.512 moles). The solution was stirred atreflux for two hours. The reaction cooled to room over 1 hour. The pHwas adjusted to 7.0 with saturate Sodium hydrogen carbonate (700 ml).The organic layer was washed with brine, dried over Magnesium sulfate,filtered and concentrated under reduced pressure. The resulting oil waschromatographed to give 77.78 g (100% crude yield) of the imino methylether as an oil.

[0511] Ex-131d) A solution of the product of Ex-131c (77.78 g, 0.409moles) in methanol (400 ml) was stirred under N₂ for 5 minutes. To thissolution was added Hydroxylamine hydrochloride (36.48 g, 0.525 moles).The reaction was stirred at reflux for 2 hours and at room temperaturefor 6 hours before the solvent was removed under reduced pressure. Theresulting brownish slurry was mixed with dichloromethane (500 ml) anddeionized water (500 ml). The pH of the water layer was adjusted to 9.0with Potassium carbonate. The solution stirred I hour under N₂. Theorganic layer was separated, dried over Magnesium sulfate, filtered, andevaporated under reduced pressure to afford the hydroxamidine (74.30 g,98% crude yield).

[0512] Ex-131e) A solution of the product of Ex-131d (74.30 g, 0.399moles) in dichloromethane (500 ml) was placed in an ice bath and stirredunder N₂ for 20 minutes. To this solution was added a suspension of1,1-carbonyldiimidazole (82.90 g, 0.511 moles) in dichloromethane (500ml). The reaction mixture was stirred in an ice bath under N₂ for 1hour. The reaction mixture removed from the ice bath was stirred underN₂ for 12 hours. To reaction mixture was added Potassium hydrogensulfate (500 ml, 10%) and stirred under N₂ for 1 hour. The organic layerwas separated, washed with brine, dried over Magnesium sulfate, filteredand evaporated under reduced pressure. The crude product waschromatographed to yield 35.53 g (41%) of the oxadiazolinone as a whitesolid.

[0513]¹H NMR (CDCl₃, 300MHz) d 1.2-1.3 (m, 2H), 1.6-1.8 (m, 1H), 1.9-2.0(m, 2H), 2.3-2.5 (m, 2H), 2.7-2.9 (dd, 1H), 3.7 (s, 3H), 4.8 (m, 1H)

[0514]¹³C NMR (CDCl₃, 300 MHz) d 24.86, 26.20, 26.48, 30.40, 53.30,56.18, 159.03, 161.17, 169.32

[0515] Melting Point (Mettler FP900) 69.7-74.1° C.

[0516] Ex-131f) A solution of the product of Ex-131e (17.47 g, 0.082moles) in Tetrahydrofuran (300 ml) stirred under N₂ for 5 minutes. Tothis solution was added Lithium borohydride (51.0 ml, 0.103 moles). Thereaction stirred under N₂ for 90 minutes. The solvent was removed underreduced pressure. The white residue was dissolved in Ethyl acetate (200ml) and Potassium hydrogen sulfate (200 ml, 10%). The organic layer wasseparated, washed with brine, dried over Magnesium sulfate, filtered andevaporated under reduced pressure. The resulting residue waschromatographed to yield 14.2 g (94%) of the hydroxymethyl product.

[0517]¹H NMR (CDCl₃, 300 MHz) d 1.5-1.6 (m, 1H), 1.6-1.9 (m, 3H),1.9-2.0 (m, 1H), 2.1-2.2 (m, 1H), 2.6-2.7 (dt, 1H), 2.8-2.9 (dd, 1H),3.1 (s, 1H), 3.8-3.9 (d, 2H), 4.1-4.2 (m, 1H)

[0518]¹³C NMR (CDCl₃, 300 MHz) d 25.04, 25.28, 25.97, 29.50, 56.46,62.24, 160.16, 161.10

[0519] Melting Point (Mettler FP900) 105.9-108.5° C.

[0520] Ex-131g) To a solution of the product of Ex-131f (5.6 g, 0.030moles) in dichloromethane (125 ml) was added Carbon tetrabromide (15.27g, 0.046 moles). The reaction vessel was place in an ice bath andstirred for 30 minutes under nitrogen. To this mixture was addedTriphenylphosphine (16.07 g, 0.061 moles). The mixture stirred 1 hourunder nitrogen. The mixture was removed from the ice bath and stirred atroom temperature under nitrogen for 12 hours. The solvent was removedunder reduced pressure. The brown residue was triturated with ether (300ml). The solvent was removed under reduced pressure. The residue waschromatographed to yield 6.70 g of the bromomethyl product.

[0521]¹H NMR (CDCl₃, 300 MHz) d 1.5-1.6 (m, 1H), 1.6-1.9 (m, 3H),1.9-2.0 (m, 1H), 2.1-2.2 (m, 1H), 2.6-2.7 (dt, 1H), 2.8-2.9 (dd, 1H),3.4-3.5 (d, 2H), 4.4 (m, 1H)

[0522]¹³C NMR (CDCl₃, 300 MHz) d 23.48, 25.21, 26.03, 29.85, 30.29,54.63, 159.19, 160.05

[0523] Ex-131h) To a solution of Boc L-cysteine (5.1 g, 0.023 moles) inDimethylformamide (70 ml) was added Sodium hydride (1.92 g, 0.048 moles)and stirred under nitrogen for 15 minutes. To this solution was added asolution of the product of Ex-13g (5.0 g, 0.020) in Dimethylformamide(30 ml). The reaction stirred 12 hours under nitrogen. The reaction wasquenched with Potassium hydrogen sulfate (300 ml, 10%). The solution wasconcentrated under reduced pressure. The residue was purified by reversephase HPLC to yield 7.0 g (91 %) of the title product as a white fluffy,hydroscopic solid.

[0524]¹H NMR (CDCl₃ , 300 MHz) d 1.4-1.6 (s, 9H), 1.7-2.3 (m, 5H),2.4-2.6 (t, 1H), 2.8-3.2 (m, 4H), 4.2-4.6 (m, 2H), 5.2-5.4 (m, 3H).

EXAMPLE 132 S-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-L-cysteine, monohydrochloride

[0525]

[0526] Ex-132) A solution of the product from Ex-131 (1.32 g 0.0034moles) was treated with 2 N HCl (8 ml), the pH was adjusted to 2, andstirred under N₂ for 1 hour. The product was purified by reverse phaseHPLC and then lyophilized to give 0.78 g (79.6%) of the title product asa white solid.

[0527]¹H NMR (CDCl₃, 300 MHz) d 1.7-2.3 (m, 5H), 2.4-2.6 (t, 1H),2.8-3.2 (m, 4H), 4.2-4.6 (m, 2H), 5.2-5.4 (m, 3H).

EXAMPLE 133 3-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]sulfinyl]-L-alanine, monohydrochloride

[0528]

[0529] Ex-133) A solution of the product from Ex-132 (0.039 g 0.00012moles) in deionized water (5 ml) was placed in an ice bath and stirredunder nitrogen for 30 minutes. To this solution was added Hydrogenperoxide (0.25 ml, 0.00012 moles) in formic acid (0.25 ml). The reactionvessel stirred in an ice bath under nitrogen for 1.5 hours. The reactionmixture continued to stir while the solution warmed to room temperature.Product was purified on reverse phase HPLC to give 0.030 g (75%) of thetitle product as a thick yellow oil.

[0530]¹H NMR (CDCl₃ , 300 MHz) d 1.4-1.6 (m, 6H), 2.4-2.5 (m, 1H)2.6-2.7 (m, 1H), 3.1-3.2 (m, 4H), 3.3-3.4 (m, 3H), 3.6-3.7 (m, 1H),4.0-4.2 (m, 2H)

EXAMPLE 134 3-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]sulfonyl]-L-alanine, monohydrochloride

[0531]

[0532] Ex-134) A solution of Hydrogen peroxide (10 ml, 0.009 moles) informic acid (10 ml) was placed in an ice bath, under nitrogen andstirred 30 minutes. To this solution a solution of the product of Ex-132(1.0 g, 0.0031 moles) in deionized water (15 ml) was added. The reactionvessel remained in the ice bath, stirring, for 2 hours. The reactionvessel was removed from the ice bath and stirred while warming to roomtemperature. The reaction solution was lyophilized to afford 1.03 g(94%) of the title product as a yellow solid.

[0533]¹H NMR (CDCl₃, 300 MHz) d 1.4-1.9 (m, 6H), 2.5-2.8 (m, 3H),3.5-4.1 (m, 4H) 4.2-4.4 (m, 1H)

EXAMPLE 135 methyla-(acetylamino)-6,7,8,9-tetrahydro-g,3-dioxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate

[0534]

[0535] Ex-135a) A sample of 2-nitroethanol (10 g, 110 mmol) was addedover a period of 30 minutes to a mixture of sodium acetate (2.5 g) andacetic anhydride (13 g, 127 mmol) cooled in ice bath and maintainedunder a N₂ atmosphere. After 1 hour of stirring, the ice bath wasremoved and the mixture was stirred for 12 hours at room temperature.The reaction was diluted with 200 mL water and extracted with 3×100 mLEtOAc. The combined extracts were washed with brine, dried (MgSO₄) andstripped of all solvent in vacuo to afford the 2-nitro ethylacetate as aclear oil.

[0536] Ex-135b) The product of Ex-135a (13.3 g, 100 mmol) was dissolvedin 15 mL acetonitrile which was added to a solution of 1 morpholinocyclohexene (18.4 g, 110 mmol) in 30 mL AcCN at −20° C. under N₂. Afterthe addition was complete stirring was continued for 16 hours at roomtemperature. After 40 mL of 1 N HCl was added to the solution, stirringwas continued for 4 more hours. The mixture was diluted with 100 mLwater and extracted with 3×100 mL EtOAc. The combined organic phase waswashed with brine, dried (MgSO₄) and evaporated in vacuo to yield 14.5 g2-(2-nitro ethyl)cyclohexanone as dark oil (85% overall yield).

[0537] Mass spectral analysis for C₈H₁₃NO₃: M⁺H=172 and M⁺Li=178.

[0538] Ex-135c) The product of Ex-135b (3.42 g, 20 mmol) in 25 mL formicacid was refluxed for 30 minutes in the presence of H₂N—OSO₃H (2.48 g,22 mmol). The formic acid was removed in vacuo. The residual oil wasdissolved in a mixture of water (40 mL) and AcCN (10 mL) and the isomerswere separated on preparative HPLC using AcCN/H₂O (0.05% TFA) gradient(10-25% AcCN in 30 minutes) to yield 7-(2-nitroethyl)caprolactam: 1.95 g(52%).

[0539] Mass spectral analysis for C₈H₁₄N₂O₃: M⁺H=187.

[0540] Ex-135d) 7-(2-nitroethyl)caprolactam (5.5 g; 0.03 mol) wascombined with trimethyloxonium tetrafluoroborate (5.0 g; 0.033 mol) anddissolved/suspended in 50 ml of CH₂Cl₂. The mixture was stirred for 18hours, affording a clear solution. Saturated NaHCO₃ (50 mL) was addedand the mixture stirred until gas evolution ceased and the pH wasgreater than 8. The layers were separated, the organic phase dried overMgSO₄ and concentrated in vacuo to yield 5.8 g of the iminoether as anoil.

[0541] Ex-135e) The product of Ex135-d was combined with hydroxylaminehydrochloride (4.2 g; 0.028 mol) and ethanol (50 mL) then stirred atreflux for one hour. The mixture was cooled and concentrated in vacuo.The residue was partitioned between saturated NaHCO₃/CH₂Cl₂. The organiclayer was dried over MgSO₄ and concentrated in vacuo to yield thehydroxamidine as an oil.

[0542] Ex-135f) The product of Ex-135e was combined with1,1′-carbonyldiimidazole (4.5 g; 0.028 mol), dissolved in 50 mL ofCH₂Cl₂, and stirred for 18 hours. The reaction mixture was washed with10% KHSO₄ to remove excess imidazole. The organic solution was driedover MgSO₄ and concentrated in vacuo. The residue was chromatographed onMerck silica, eluting with 40% EtOAc/hexane. The desired product elutedfirst off the column and crystallized upon concentration to yield 3.1 gof the oxadiazolinone as a white powder.

[0543] Mass spectra for C₉H₁₃N₃O₄, M+H=228

[0544]¹H NMR (CDCl₃) d 1.4 to1.6, m (1H); 1.75 to 1.86, m (2H); 1.95 to2.19, m (3H); 2.28 to 2.39, m (1H); 2.48 to 2.62, m (2H); 2.91 to 2.98 &2.98 to 3.01, d of d of t (1H); 4.28 to 4.38, m (1H); 4.38 to 4.54, m(2H).

[0545] Ex-135h) The product of Ex-135f (5.0 g; 0.022 mol) was combinedwith methyl N-acetylacrylate (3.2 g; 0.024 mol) and tetramethylguanidine(0.55 mL) in 50 mL of CH₂Cl₂. The reaction mixture was heated at refluxfor 36 hours. The reaction mixture was concentrated and the residue waschromatographed on silica eluting with EtOH/EtOAc to afford twoproducts. The more polar component was isaolated to afford 1 g of thetitle product.

[0546] Mass spectra for C₁₅H₂₁N₃O₆, M+H=340

[0547]¹H NMR (CDCl₃) d 1.49, t (1H); 1.55 to 1.85, m (2H); 1.85 to 2.05,m (2H); 2.05, t (3H); 2.38 to 2.45, m (2H); 2.48 to 2.72, m (2H); 2.88to 2.98, d of d (1H); 3.44, s (1 H); 3.72, s (3H); 4.25 to 4.34, m (1H);4.55 to 4.7, m (2H).

EXAMPLE 136 methyla-(acetylamino)-g,g-difluoro-6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate

[0548]

[0549] Ex-136) The product of Ex-135 (200 mg; 0.00059 mol) is dissolvedin CH₂Cl₂ (5.0 mlL) and (diethylamino)sulfur trifluoride (DAST) (190 mg:0.0018 mol) is added and the reaction mixture is stirred for 18 hours.The reaction is quenched with water. The organic layer is dried overMgSO₄ and concentrated to afford the title product.

EXAMPLE 137 methyla-(acetylamino)-6,7,8,9-tetrahydro-g-nitro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate

[0550]

[0551] Ex-137) The less polar component from Ex-135 was isolated toafford 5 g of the title product.

[0552] Mass spectra for C₁₅H₂₂N₄O₇, M+H=371

[0553]¹H NMR (MeOD) d 1.5, t (1H); 1.7 to 2.9, m (3H); 1.95 to 2.2, m(7H); 2.25 to 2.8, m (4H); 2.95, t (1H); 3.7 to 3.8, m (3H); 4.2 to4.75, m (3H); 6.35 to 6.6, m (1H).

EXAMPLE 138 methyla-(acetylamino)-6,7,8,9-tetrahydro-g-methylene-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate

[0554]

[0555] Ex-137) Methyltriphenylphosphonium bromide (360 mg; 0.001 mol) isdissolved/suspended in THF (5.0 mL) then cooled to −78° C. n-BuLi isadded and the temperature is raised to −40° C. for one hour. The mixtureis recooled to −78° C. and the product of example 11 (200 mg; 0.00059mol) is dissolved in THF and added to the mixture. The reaction mixtureis allowed to warm to room temperature. Saturated NH₄Cl (5.0 ml) isadded and the mixture is stirred for one hour. The organic layer isseparated and dried over MgSO₄ and concentrated. The residue ischromatographed on silica gel. Elution with EtOAc/hexane affords thetitle product.

EXAMPLE 139N-[(1,1-dimethylethoxy)carbonyl]-3-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]amino]-L-alanine

[0556]

[0557] Ex-139a) A solution of 8 mL (16 mmol) 2M oxalylchloride in CH₂Cl₂was diluted with 15 mL CH₂Cl₂. This solution was cooled to −60° C. and 5mL (70 mmol) of DMSO was added. After 5 minutes, 2.1 g (11.4 mmol) ofthe product of example 7f in 50 ml CH₂Cl₂ was added to the mixture.After 30 minutes stirring at −60° C. 10 mL (72 mmol) triethylamine wasadded to the reaction mixture and stirring was continued for 18 hours atroom temperature. The reaction mixture was then diluted with 200 mLCH₂Cl₂ and washed with 2×100 mL 10% KHSO₄ and brine. The organic phasewas dried over MgSO₄ and the solvent was evaporated to afford thealdehyde as an oil, 2 g (96%).

[0558] Mass spectrak analysis for C₈H₁₀N₂O₃: M+H=183.

[0559] Ex-139) A solution of 2 g (11 mmol) of the product of Ex-139a wasdissolved in 15 mL DMF (containing 0.15 mL acetic acid) and allowed toreact with 2.2 g (11 mmol) N-a-Boc-L-diaminopropionic acid. After 15minutes stirring, 1.25 g (20 mmol) NaCNBH₃ was added and stirring wascontinued for 18 hours. The DMF was evaporated in vacuo and the residuewas dissolved in 100 mL ethyl acetate. This solution was washed with2×50 mL 10% KHSO₄ and brine. The organic phase was dried over MgSO₄,filtered and the solvent was evaporated in vacuo to afford the titleproduct as an oil, 3.7 g (91%).

[0560] Mass spectral analysis for C16H26N4O6: M+H=371.

EXAMPLE 140 methyl(2S,4Z)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-6-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-hexenoate

[0561]

[0562] Ex-140) The product of Ex-149 is allowed to stir at reflux inmethanol containing a catalytic amount of acid. Evaporation of thesolvent in vacuo affords the title product.

EXAMPLE 141(3Z)-2-amino-6-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-hexenoicacid

[0563]

[0564] Ex-141a) A solution of BH₃ (1M)(26 mL) in THF was cooled to 0° C.in an ice bath. To this solution was added a solution of the product ofEx125e (5.0 g, 0.025 mol) in dry THF (25 mL) drop wise via an additionfunnel. The reaction stirred at 0° C. for 2.5 hours. To the reaction wasadded a 3% hydrogen peroxide at a pH of 10, adjusted by potassiumcarbonate. After 60 minutes, ethyl acetate(50 mL) was added and waspartitioned between brine(50 mL). The organics were collected and driedover magnesium sulfate anhydrous then removed under reduced pressure.The pale yellow oil was purified by flash chromatography using 1:1 ethylacetate:hexane to afford hydroxypropyl product(2.42 g) in 44% yield.

[0565]¹H NMR (CDCl₃, 300 MHz) d 1.4-2.2(m, 11H), 2.51 (t, 1H), 2.89(dd,1H), 3.61(q, 2H), 4.25(m, 1H).

[0566] Ex-141b) The procedure of Ex-125g was utilized with the productof Ex-141a to afford the bromopropyl product in 98% yield.

[0567]¹H NMR (CDCl₃, 300 MHz) d 1.38-2.15(m, 11H), 2.51 (t, 1H),2.95(dd, 1H), 3.42(m, 2H), 4.21(m, 1H).

[0568] EX-141c) The procedure of Ex-125h was utilized with the productof Ex-141b to afford the phosphonium bromide in 98% yield.

[0569]¹H NMR (CDCl₃, 300 MHz) d 1.38-2.61(m, 9H), 2.85 (dd, 1H), 3.60(m,1H), 3.19(m, 1H), 4.45(m, 1H), 7.60-7.9(m, 15H).

[0570] Ex-141d) To a 50 mL 3-neck round bottom flask fitted with anaddition funnel was added the product of Ex-141c (4.93 g, 0.009 mol) in20 mL of THF. The solution was cooled to −78° C. in a dry ice bath. Tothis solution was added potassium bis(trimethylsilyl)amide (0.5M)(10 mL,0.020 mol) slowly so that the temperature would not raise above −72° C.The reaction stirred at −78° C. for 15 minutes. To the reaction wasadded Garner's Aldehyde (2.62 g, 0.012 mol) drop wise so that thetemperature did not raise above −72° C. The reaction stirred for anadditional 45 minutes then the dry ice bath was removed and stirred atroom temperature for 4 hours. To the reaction was added a saturatedsolution of ammonium chloride. The organics were collected and washedwith brine(3×25 mL), dried over magnesium sulfate anhydrous, removedunder reduced pressure. The product was purified utilizing flashchromatography with 30:70 ethyl acetate:hexane to afford the protectedamino alcohol (1.02 g, 0.002) in 39.9% yield.

[0571]¹H NMR (CDCl₃, 300 MHz) d 1.49(s, 9H), 1.59-3.0 (m,.15H), 3.65(d,1H), 4.1(m, 2H), 4.3(m, 1H), 4.6(bs, 1H), 5.40(m, 2H).

[0572] Mass Spec m/z 208.2(M+H), m/z 430.2(M+Na), m/z 308.2(M+H−100).

[0573] Ex-141e) To a solution of the product of Ex-141d (1 g, 0.003 mol)in methylene chloride(20 mL) was added triflouroacetic acid(4 mL). Thereaction stirred for two hours then a solution of 5% potassium carbonatewas added. The organics were collected and washed with brine(3×20 mL),dried over magnesium sulfate anhydrous, removed under reduced pressure.To the resulting residue was added acetone(20 mL). To this solution wasadded Jone's Reagent(8N, 20 drops). After 2 hours, the reaction wasmonitored by TLC and starting material remained. Twenty additional dropswere pipetted in and the reaction stirred over night. To the reactionwas added methanol(10 mL). To the slurry was added water (100 mL) andthe reaction was purified by reverse phase chromatography to afford thetitle product.

EXAMPLE 142 a-amino-6,7-dihydro-3-oxo-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazole-5-pentanoic acid

[0574]

[0575] Ex-142a) 5-methoxy-2-pyrrolidinone is allowed to react withpentenyl magnesium bromide in THF at reflux for 3 h. The reactionsolution is queched with saturated aqueous ammonium chloride andextracted with EA. The 5-(but-4-enyl)-2-pyrrolidinone is purified bycolumn chromatography on silica gel.

[0576] Ex-142b) A portion of the product of Ex-142a is allowed to reactwith of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16 hourperiod. The mixture is diluted with CH₂Cl₂ and washed with 5% NaHCO₃ andbrine. The organic phase is dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0577] Ex-142c) The product of Ex-142b is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0578] Ex-142d) The product of Ex-142c is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Theproduct is purified by column chromatography on silica gel.

[0579] Ex-142e) A steam of ozone is allowed to pass through a CH₂Cl₂solution of the product of Ex-142d until a blue color persists. A streamof argon is then allowed to pass through the reaction solution for 15min. followed by the addition of Me₂S. The solution is allowed to stirat rt overnight. The solvent is removed under reduced pressure to yieldthe aldehyde.

[0580] Ex-142f) DBU is added to a solution ofZ-phosphonoglycinetrimethylester in CH₂Cl₂. A solution of Ex-142e CH₂Cl₂is then added, and the resulting mixture is allowed to stir overnight atrt. The reaction mixture is then diluted with CH₂Cl₂ and extracted withHCl (1M) and brine. The product is purified by column chromatography onsilica gel.

[0581] Ex-142g) Catalytic Rh(R,R-DIPAMP) is allowed to react with asolution of Ex-142f in MeOH under an atmosphere of H₂ at 60 psi and 50°C. for 20 h. The product is purified by column chromatography on silicagel.

[0582] Ex-142h) The product of Ex-142h is hydrolyzed in 10% hydrochloricacid at reflux followed by concentration under reduced pressure. Theresulting crude product residue is dissolved in water and extracted withdiethyl ether. The title compound is isolated from the reaction mixtureusing C₁₈ reverse phase HPLC.

EXAMPLE 143 a-amino-6,7-dihydro-3-oxo-6-(trifluoromethyl)-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazole-5-pentanoic acid

[0583]

[0584] Ex-143a) 2-(3-nitro-propyl)-[1,3]dioxolane is prepared by themethod of Knefeli et.al., Arch.Pharm. 316; 9; 1983; 773-781.2-(3-nitro-propyl)-[1,3]dioxolane is then allowed to react withethyl-4,4,4-trifluorocrotonate and DBU in acetonitrile at rt over a 16 hperiod. The solvent is removed and the residue is taken up in EA andextracted with KHSO₄ (10%) and brine. The solvent is evaporated invacuo. The residue in MeOH is allowed to reduce under a H₂ atmosphere inthe presence of Pd/C 10% at 60 psi and 50° C. The solvent is evaporatedin vacuo. The product is purified by column chromatography on silicagel.

[0585] Ex-143b) A portion of the product of Ex-143a is allowed to reactwith of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16 hourperiod. The mixture is diluted with CH₂Cl₂ and washed with 5% NaHCO₃ andbrine. The organic phase is dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0586] Ex-143c) The product of Ex-143b is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0587] Ex-143d) The product of Ex-143d is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Theproduct is purified by column chromatography on silica gel.

[0588] Ex-143e) The product of Ex-143d is allowed to react with AcOH:H₂O(70:30)for 16 hours at 70° C. The solvent is evaporated to afford thealdehyde.

[0589] Ex-143f) DBU is added to a solution ofZ-phosphonoglycinetrimethylester in CH₂Cl₂. A solution of 143c CH₂Cl₂ isthen added, and the resulting mixture is allowed to stir overnight atrt. The reaction mixture is then diluted with CH2Cl2 and extracted withHCl (1M) and brine. The product is purified by column chromatography onsilica gel.

[0590] Ex-143g) Catalytic Rh(R,R-DIPAMP) is allowed to react with asolution of 143f in MeOH under an atmosphere of H₂ at 60 psi and 50° C.for 20 h. The product is purified by column chromatography on silicagel.

[0591] Ex-143) The product of Ex-143g is hydrolyzed in 10% hydrochloricacid at reflux followed by concentration under reduced pressure. Theresulting crude product residue is dissolved in water and extracted withdiethyl ether. The title compound is isolated from the reaction mixtureusing C₁₈ reverse phase HPLC.

EXAMPLE 144 a-amino-5-(6,7-dihydro-3-oxo-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazol-5-yl)-2-furanacetic acid

[0592]

[0593] Ex-144a) 5-methoxy-2-pyrrlidinone is allowed to react with furanwith catalytic PTSA in CH₂Cl₂ for 6 h at rt . The5-furan-2-yl-pyrrolidin-2-one 144a is purified by column chromatographyon silica gel.

[0594] Ex-144b) A portion of the product of Ex-144a is allowed to reactwith of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16 hourperiod. The mixture is diluted with CH₂Cl₂ and washed with 5% NaHCO₃ andbrine. The organic phase is dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0595] Ex-144c) The product of Ex-144b is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0596] Ex-144d) The product of Ex-144c is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Theproduct is purified by column chromatography on silica gel.

[0597] Ex-144e) The product of Ex-144d is allowed to react with ethyl2-acetoxy-2-diphenylmethyleneaminoacetate and TiCl₄ in CH₂Cl₂ at rt for4 h. The reaction mixture is quenched and treated with aqueous HCl (1M).The product is isolated from the reaction mixture using C₁₈ reversephase HPLC.

[0598] Ex-144f) The product of Ex-144e is allowed to hydrolyze in EtOHand aqueous LiOH. The reaction solution is acidified and concentrated invacuo. The product is isolated from the reaction mixture using C₁₈reverse phase HPLC.

EXAMPLE 145 a-amino-3-(6,7-dihydro-3-oxo-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazol-5-yl)-2-benzeneacetic acid

[0599]

[0600] Ex-145a) Magnesium is allowed to react with2-(3-bromo-phenyl)-[1,3]-dioxolane in THF to form the Gringard.5-methoxy-2-pyrrolidinone is allowed to react with the Gringard in THFat reflux for 3 h. The reaction solution is quenched with saturatedaqueous ammonium chloride and extracted with EA. The product is purifiedby column chromatography on silica gel.

[0601] Ex-145b) A portion of the product of Ex-145a is allowed to reactwith of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16 hourperiod. The mixture is diluted with CH₂Cl₂ and washed with 5% NaHCO₃ andbrine. The organic phase is dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0602] Ex-145c) The product of Ex-145b is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0603] Ex-145d) The product of Ex-145c is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Theproduct 145d is purified by column chromatography on silica gel.

[0604] Ex-145e) The product of Ex-145e is allowed to react with AcOH:H₂O(70:30)for 16 hours at 70° C. The solvent is evaporated to afford thealdehyde.

[0605] Ex-145f) The product of Ex-145e is allowed to react with KCN andNH₄Cl followed by hydrolysis in aqueous H₂SO₄. The product is isolatedfrom the reaction mixture using C₁₈ reverse phase HPLC.

EXAMPLE 146a-amino-4,5,5a,6,7,8,9,9a-octahydro-5-methyl-1-oxo-1H-[1,2,4]-oxadiazolo[4,3-a]quinoline-9-butanoicacid

[0606]

[0607] Ex-146a) 2-allyl-aniline is allowed to react withmethylacetoacetate at 140° C. in a sealed vessel. The product ispurified by column chromatography on silica gel.

[0608] Ex-146b) The product 146a is allowed to react in concentratedH₂SO₄. The reaction mixture is poured onto water and the pH is adjustedto 7. The product is collected by filtration.

[0609] Ex-146c) A steam of ozone is allowed to pass through a CH₂Cl₂solution of the product of Ex-146b until a blue color persists. A streamof argon is then allowed to pass through the reaction solution for 15min. followed by the addition of Me₂S. The solution is allowed to stirat rt overnight. The solvent is removed under reduced pressure to yieldthe aldehyde.

[0610] Ex-146d) A solution of the aldehyde is allowed to react withanhydrous methanol, PTSA and trimethylorthoformate for 16 h at rt. Theproduct 146d is purified by column chromatography on silica gel.

[0611] Ex-146e) A mixture of the product of Ex-146d and platinum oxidein methanol is hydrogented at room temperature and 50 psi. The catalystis filtered washed with methanol and concentrated. The desired lactam126c is purified by column chromatography on silica gel.

[0612] Ex-146f) A portion of the product of Ex-146e is allowed to reactwith of trimethyloxonium tetrafluoroborate in CH₂Cl₂ over a 16 hourperiod. The mixture is diluted with CH₂Cl₂ and washed with 5% NaHCO₃ andbrine. The organic phase is dried over MgSO₄, filtered and the solventwas evaporated in vacuo to afford the iminoether.

[0613] Ex-146g) The product of Ex-146f is allowed to react withhydroxylamine hydrochloride in MeOH for 16 hours. The methanol isevaporated to afford the hydroxamidine.

[0614] Ex-146h) The product of Ex-146g is allowed to react with1,1′-carbonyldiimidazole in CH₂Cl₂ for 24 hours at room temperature. Theproduct 145d is purified by column chromatography on silica gel.

[0615] Ex-146i) The product of Ex-145h is allowed to react with AcOH:H₂O(70:30)for 16 hours at 70° C. The solvent is evaporated to afford thealdehyde.

[0616] Ex-146j) DBU is added to a solution ofZ-phosphonoglycinetrimethylester in CH₂Cl₂. A solution of 146i CH₂Cl₂ isthen added, and the resulting mixture is allowed to stir overnight atrt. The reaction mixture is then diluted with CH₂Cl₂ and extracted withHCl (1M) and brine. The product is purified by column chromatography onsilica gel.

[0617] Ex-146k) Catalytic Rh(R,R-DIPAMP) is allowed to react with asolution of 146j in MeOH under an atmosphere of H₂ at 60 psi and 50° C.for 20 h. The product is purified by column chromatography on silicagel.

[0618] Ex-146l) The product of Ex-146k is hydrolyzed in 10% hydrochloricacid at reflux followed by concentration under reduced pressure. Theresulting crude product residue is dissolved in water and extracted withdiethyl ether. The title compound is isolated from the reaction mixtureusing C₁₈ reverse phase HPLC.

EXAMPLE 147 5-amino-2-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-1H-imidazole-4-carboxylic acid,monohydrochloride

[0619]

[0620] Ex-147a) To a solution of the product of Ex-125e in dioxane (200mL) and water (135 mL) was added sodium periodate (15.11 g, 0.071 mol)and osmium tetraoxide (12 drops of a 1 ppm solution of osmium dioxide inn-BuOH/H₂O). The reaction was stirred at room temperature and monitor bythin layer chromatography for one day. Since the starting material hadnot completely reacted, additional osmium tetraoxide (12 drops of 1 ppmsolution of osmium dioxide in n-BuOH/H₂O) was added. A white precipitatewas filtered off and the filtrate was removed under reduced pressure tothe point where no dioxane remained. Additional water (75 mL) was thenadded to the aqueous layer and this aqueous mixture was washed withCH₂Cl₂ (3×75 mL). The organic layer was combined, dried over magnesiumsulfate, and stripped of all solvent under reduced pressure to afford ayellow oil. Chromatographic (silica gel) purification of this materialeluting with the 1:1, ethyl acetate:hexane afforded 4.0 g (67%) of thealdehyde.

[0621]¹H NMR (CDCl₃, 300 MHz) d 1.2-2.5 (m, 6H), 2.59 (q, 2H), 2.92 (m,2H), 4.79 (m, 1H), 9.79 (ss, 1H).

[0622]¹³C NMR (CDCl₃, 75 MHz) d 24.12, 31.52, 32.00, 45.61, 49.10,53.98, 159.9, 160.8, 198.1.

[0623] Ex-147b) To a solution of the product from Ex-147a in acetone isadded Jones reagent until the red color persists as described in J.Chem. Soc. 1956, 39. The reaction is then quenched with isopropylalcohol and concentrated under reduced pressure. The residue is thenpartitioned between brine and methylene chloride. The organic layer isback washed with a solution of sodium carbonate. The water layer is thenacidified with concentrated hydrochloric acid and the precipitate isfiltered and washed with water to afford the carboxylic acid.

[0624] Ex-147c) To a solution of the product of Ex-147b in methylenechloride is added a catalytic amount of DMF. Oxalyl chloride is addeddropwise at room temperature and evolution of gas is observed. Thereaction is followed by thin layer chromatography to determine when thereaction is complete. The completed reaction is concentrated underreduced pressure and the residue is dissolved in methylene chloride. Thereaction mixture is cooled to 0° C. in an ice bath and ammonia isbubbled through it. The solvent is the removed under reduced pressureand the product is partitioned between brine and methylene chloride. Theorganic is dried over magnesium sulfate and solvent is removed underreduced pressure to afford the carboxamide.

[0625] Ex-147d) To a solution of the product of Ex-147c in methylenechloride is added triethylamine. The reaction is cooled to 0° C. in anice bath and 12% phosgene in toluene is added dropwise. The reaction isstirred until completed as noted by thin layer chromatography. Thereaction is washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude residue ischromatographed to afford the nitrile.

[0626] Ex-147e) To a solution of ethanol saturated with hydrogenchloride is added portion-wise the product of Ex-147d. The reaction isallowed to warm to room temperature and is followed by thin layerchromatography. The completed reaction is concentrated and the residueis dissolved in ethanol to afford a solution of the ethyl acetimidate.

[0627] Ex-147f) The product of Ex-147e is converted to the 2-amino,3-ethoxycarbonyl-1,4-imidazol-1-yl utilizing the procedure published inJ. Chem Soc. 1949, 1071.

[0628] Ex-147g) The product of Ex-147f is hydrolyzed in 10% hydrochloricacid at reflux followed by concentration under reduced pressure. Theresulting crude product residue is dissolved in water and extracted withdiethyl ether. The product is purified on an ion exchange resin toproduce the title product.

EXAMPLE 148a-amino-6,7,8,9-tetrahydro-e-1H-imidazol-2-yl-3-oxo-3H,5H-[1,2,4]-oxadiazolo[4,3-a]azepine-5-hexanoicacid

[0629]

EXAMPLE 149 phenylmethyl(2S,4Z)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-6-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-hexenoate

[0630]

[0631] Ex-149) To a 50 mL 3-neck round bottom flask fitted with anaddition funnel was added the product of Ex-125h (1.93 g, 0.004 mol) in20 mL of THF. The solution was cooled to −78° C. in a dry ice bath. Tohe solution was added potassium bis(trimethylsilyl)amide (0.5M)(7.62 mL,0.004 mol) slowly so that the temperature would not raise above −72° C.The reaction stirred at −78° C. for 15 minutes. To the reaction wasadded the product of example 5c (1.17 g, 0.004 mol) dropwise so that thetemperature did not raise above −72° C. The reaction stirred for anadditional 45 minutes then the dry ice bath was removed and stirred atroom temperature for 4 hours. To the reaction was added a saturatedsolution of ammonium chloride. The organics were collected and washedwith brine(3×25 mL), dried over magnesium sulfate anhydrous, removedunder reduced pressure. The product was purified utilizing flashchromatography with 30:70 ethyl acetate:hexane to afford the titleproduct (1.02 g, 0.002) in 57% yield.

[0632]¹H NMR (CDCl₃, 300 MHz) d 1.38(s, 9H), 1.4-2.6 (m,.10H), 2.92(d,1H), 4.17(m, 1H), 4.38(m, 1H), 5.05(q, 2H), 5.40(m, 2H), 7.3(s,5H).

[0633]¹³C NMR (CDCl₃, 75 MHz) d 24.38, 25.0, 25.88, 26.54, 26.57, 28.73,28.74, 30.11, 31.55, 54.04, 54.13, 67.60, 67.63, 127.3, 127.4, 128.2,128.3, 128.8, 135.7, 159.9, 160.8, 172.1.

EXAMPLE 150 3-[ethyl[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]amino]-L-alanine

[0634]

[0635] Ex-150) A solution of 0.4 g (1 mmol) of the product from Ex-157is dissolved in 25 mL 1 N HCl and the mixture is stirred for 8 hours atroom temperature. The reaction mixture is diluted with 200 mL H₂O andpurified on preparative HPLC using acetonitrile/H₂O (0.05% TFA) gradientfrom 0-40% AcN in 30 minutes to afford the title product.

EXAMPLE 151(2S)-2-[[(phenylmethoxy)carbonyl]amino]-4-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)carbonyl]amino]butanoicacid

[0636]

[0637] Ex-151a) Potassium hydroxide (2.27 g, 0.040 mol) was dissolved in31 ml THF and 25 ml deionized water and cooled to 5° C. The product ofEx-131e (5.00 g,0.202 mol) was dissolved in 20 ml THF and slowly addedto the KOH/water/THF solution while stirring vigorously to preventfreezing. After stirring at reduced temperature for 2 hours, the mixturewas transferred to a stirring mixture of 200 ml toluene and 50 ml 1 Npotassium bisulfate. The layers were separated and the organics weretreated with magnesium sulfate, filtered and solvent was removed underreduced pressure to afford 4.5 g of the acid.

[0638]¹³C NMR (CDCl₃, 400 MHz) d 25.21, 26.49, 26.70, 30.62, 56.42,159.95, 161.61, 170.73

[0639] Ex-151b) The product of Ex-151a (1.00 g, 0.0047 mol) wasdissolved in methylene chloride (10 ml) and charged with1,1′-carbonyldiimidazole (0.835 g, 0.005 mol). After stirring for 5minutes, diaminobutyric acid (1.30 g, 0.005 mol) was added and thereaction mixture was stirred overnight (20 hours). The reaction wastransferred into a stirring mixture of 50 ml 1 N potassium bisulfate and200 ml toluene. The layers were separated, and the organic phase wastreated with saturated sodium bicarbonate, then solid magnesium sulfate.This was filtered through a sintered glass funnel, and solvent wasremoved under reduced pressure to afford 295 mg (15%) of the titleproduct.

[0640] Analysis calcd. for C₂₀H₂₄N₄O₇+1.2 H₂O carbon hydrogen nitrogencalcd. 52.91 5.86 12.34 found 52.94 6.01 11.97

EXAMPLE 152N-[(phenylmethoxy)carbonyl]-O-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-L-serine

[0641]

[0642] Ex-152a) The product of Ex-131f (4.20 g, 0.0228 mol) wasdissolved in 27 ml Pyridine and 50 ml Methylene Chloride and cooled to0° C. in an ice bath under a nitrogen stream. Methane sulfonyl chloride(1.94 ml, 0.0251 mol) was added dropwise to the reaction vessel. Afteraddition, the ice bath was removed and the reaction was allowed to warmto room temperature and stirred overnight (16 hour). The solvent wasremoved under reduced pressure, and excess pyridine was azeotroped usingtoluene. The residual solid was redissolved in 200 ml ethyl acetate and50 ml 1 N potassium bisulfate. The layers were separated and the organicphase was treated with 50 ml brine. Layers were separated again, theaqueous layer was tested using thin layer chromatography (ethyl acetate,visualized by iodine) to ensure all organics were removed. The organiclayer is treated with magnesium sulfate, filtered through a sinteredglass funnel, then solvent removed under reduced pressure to afford themesylate, (4.1 g, 68%).

[0643] Elemental analysis calcd. for C₉H₁₄N₂O₅S carbon hydrogen nitrogencalcd. 41.21 5.38 10.68 found 41.29 5.73 10.45

[0644]¹³C NMR (CDCl₃, 400 MHz) d 24.48, 25.05, 25.93, 29.09, 37.97,52.63, 66.58, 159.19, 160.02

[0645] Ex-152b) N-Z-Serine (0.502 g, 0.0021 mol) was dissolved in THF(18 ml). This was cooled to 0° C. in an ice bath and slowly added SodiumHydride (0.168 g, 0.0042 mol), with vigorous stirring. After gasevolution ceases, a solution of the product of Ex-152a (0.5 g, 0.0019mol) was dissolved in THF (20 ml) and added to the Serine/NaH mixtureslowly. Another 0.168 g of Sodium Hydride was added to the mixture.After 4.5 hours of stirring at 0° C., the reaction mixture wastransferred to a stirring mixture of 50 ml 1 N potassium bisulfate, and100 ml ethyl acetate. The layers were separated, and the organic phasewas treated with magnesium sulfate, filtered and solvent removed underreduced pressure. Further chromatography using 50% ethyl acetate inhexane (visualized with iodine) produced 0.244 g (32%) of the titleproduct.

EXAMPLE 153 bis(1,1-dimethylethyl)4-nitro-4-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]heptanedioate

[0646]

[0647] Ex-153) The product of Ex-135f (227 mg; 0.001 mol) was combinedwith t-butyl acrylate (256 mg; 0.002 mol) and K₂CO₃ in 5 mL of DMF. Thereaction mixture was stirred for 18 hours. The reaction mixture was thenconcentrated and the residue partitioned between CH₂Cl₂ and water. Theorganic layer was dried over MgSO₄ then concentrated. The residuecrystallized and was triturated with Et₂O to yield 354 mg of the titleproduct as a solid. Anal. Calcd. for C₂₃H₃₇N₃O₈ C: 57.13 H: 7.75 N: 8.69Found: C: 57.24 H: 7.95 N: 8.53.

[0648] Mass Spectra for C₂₃H₃₇N₃O₈ M+NH₄=501

[0649]¹H NMR (CDCl₃) d 1.38 to1.58, m (18H); 1.6 to 2.0, m (5H); 2.1 to2.4, m (10H); 2.48 to 2.62, m (2H); 2.82 to 3.02, m (1H); 4.3 to 4.5 m(1H).

EXAMPLE 154 S-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]homocysteine

[0650]

[0651] Ex-154a) To a solution of Boc DL-homocysteine (1.90 g, 8 mmoles)in N-dimethylformamide (25 mL) was added Sodium hydride in 60% mineraloil dispersion (0.73 g, 18.3 mmoles) and stirred under nitrogen for tenminutes. To this solution was added the product from example 7g (1.8 g,7.3 mmoles) in N-dimethylformamide (10 mL). The reaction solution wasstirred for 12 hours under nitrogen at room temperature. Solution wasquenched with Potassium hydrogen sulfate (100 mL) and concentrated underreduced pressure. The product was purified by reverse phase HPLC toyield 2.08 g (71%) of Boc-protected product as a white fluffy,hydroscopic solid.

[0652] Mass Spectra for C₁₇H₂₇N₃O₆S₁: M+H=402

[0653] Ex-154b) The product from Ex-154a is dissolved in 2N HCl andallowed to stir for 4 hours. The reaction solution is diluted withde-ionized water and purified with reverse phase HPLC to afford thetitle product.

EXAMPLE 155 S-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]-L-cysteine

[0654]

[0655] Ex-155a) To a solution of Boc L-cysteine (1.16 g, 5.25 mmoles) inN-dimethylformamide (15 mL) was added Sodium hydride in 60% mineral oildispersion (0.42 g, 10.5 mmoles) and stirred under nitrogen for tenminutes. To this solution was added the product from example 1g (1.8 g,7.3 mmoles) in N-dimethylformamide (10 mL). The reaction solution wasstirred for 12 hours under nitrogen at room temperature. The solutionwas quenched with Potassium hydrogen sulfate (100 mL) and concentratedunder reduced pressure. The product was purified by reverse phase HPLCto yield 1.87 g (89%) of Boc-protected product as a white, hydroscopiccompound.

[0656] Mass Spectra for C₁₇H₂₇N₃O₆S₁: M+Na=424

[0657] Ex-155b) The product from Ex-155a is dissolved in 2N HCl andallowed to stir for 4 hours. The reaction solution is diluted withde-ionized water and purified with reverse phase HPLC to afford thetitle product.

EXAMPLE 156 S-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]homocysteine

[0658]

[0659] Ex-156a) To a solution of Boc homocysteine (0.55 g, 2.36 mmoles)in N-dimethylformamide (15 mL) was added Sodium hydride in 60% mineraloil dispersion (0.19 g, 4.68 mmoles) and stirred under nitrogen for tenminutes. To this solution was added the product from Ex-125g (0.49 g,1.88 mmoles) in N-dimethylformamide (10 mL). The reaction solution wasstirred for 12 hours under nitrogen at room temperature. The reactionsolution was quenched with Potassium hydrogen sulfate (50 mL) andconcentrated under reduced pressure. The product was purified by reversephase HPLC to yield 0.50 g (64%) of the Boc-protected product as awhite, hydroscopic compound.

[0660] Mass Spectra for C₁₈H₂₉N₃O₆S₁: M+H=416

[0661] Ex-156b) The product from ex-156a is dissolved in 2N HCl and isallowed to stir for 4 hours. The reaction solution is diluted withde-ionized water and purified with reverse phase HPLC to afford thetitle product.

EXAMPLE 157N-[(1,1-dimethylethoxy)carbonyl]-3-[ethyl[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]amino]-L-alanine

[0662]

[0663] Ex-157) To a solution of 3.7 g (10 mmol) of the product of Ex-139was dissolved in 25 mL DMF (containing 0.25 mL acetic acid). This wasallowed to react with 0.614 mL (11 mmol) of acetaldehyde with vigorousstirring for 15 minutes. To this mixture was then added 1.25 g (20 mmol)NaCNBH₃ and stirring was continued for 18 hours. The DMF was evaporatedin vacuo and the residue was dissolved in 200 mL ethyl acetate. Thissolution was washed with 2×100 mL 10% KHSO₄ and brine. The organic phasewas dried over MgSO₄, filtered and the solvent was evaporated in vacuoto afford the title product as a yellow oil, 2.1 g (52%).

[0664] Mass spectral analysis for C18H30N4O6: M+H=399.

Biological Data

[0665] The subject compounds of formula (I) have been or are expected tobe found to inhibit nitric oxide synthase and posses usefulpharmacological properties as demonstrated in one or more of thefollowing assays:

In Vivo Assay

[0666] Mice were treated with an intraperitoneal injection of 12.5 mg/kgof endotoxin (LPS) with or without oral administration of the nitricoxide synthase inhibitors. Plasma nitrites were measured 5 hourspost-treatment. The results show that the administration of the nitricoxide synthase inhibitor decreases the rise in plasma nitrites, areliable indicator of the production of nitric oxide, induced byendotoxin. TABLE I Low Dose LPS* in vivo Effective Dose (p.o., mg/kg)Compound 1 3 10 Example 1 23% inh. 72% inh. Example 3 33% inh. 64% inh.

What is claim is:
 1. A compound having the formula:

and salts, pharmaceutically acceptable esters, and prodrugs thereof,wherein: R¹ is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, C(O)R⁶,carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon and cycloalkyl, allof which may be optionally substituted by one or more of the groupsselected from lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,heterocyclyl, aryl, halogen, cyano, nitro, amino, alkylamino,dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl,alkylaminoaryl, acylamino, carboxy, carboxyalkyl, P(R⁵)₃, C(O)R⁵, OR⁵,SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substituents maybe optionally substituted with one or more selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), C(O)R⁶, carboalkoxyalkyl, cyano, nitro, amidino, andguanidino, wherein R⁵ and R⁶ of SO₂NR⁵R⁶ and NR⁵SO₂R⁶ may be takentogether to form a N-containing heterocycle, optionally substituted byone or more selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano,nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, andcarboxyalkyl; R¹ may be

wherein J is selected from the group consisting of O, S and NR; R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aromatichydrocarbon, alkylaryl, alkylheterocycle, all of which may be optionallysubstituted by one or more of alkyl, hydroxy, alkoxy, halogen,haloalkyl, cyano, amino, and nitro; NR and R²⁰ may optionally form aheterocycle; R¹⁶ is selected from the group consisting of lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵,S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino,wherein all said substituents may be optionally substituted with one ormore of the group consisting of lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, loweralkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁸, S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂,PO(OR⁸)(OR⁹), amidino, and guanidino. R¹⁷ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, alkylaryl, andalkylheterocycle, all except hydrogen may be optionally substituted byone or more of alkyl, hydroxy, alkoxy, thiol, alkylthiol, halogen,haloalkyl, carboxyl, cyano, amino, and nitro; R¹⁸ is selected from thegroup consisting of hydrogen, hydroxyl, R¹², S(O)R¹¹, SO₂R¹¹,CH₂OC(O)—R¹¹, and C(O)—R¹¹ wherein C(O)—R¹¹; R¹⁸ and R²⁰ may be takentogether to form a 5- or 6-membered heterocyclic ring containing two ormore heteroatoms which may be optionally substituted by one or more ofR¹⁶; R² and L may be taken together to form a 3 to 9 membered alicyclicor heterocyclic ring which may be optionally substituted by one or moreof R¹⁶; R² and R¹⁷ may be taken together to form a 4 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶; R² and R¹⁸ may be taken together to form a 6 to 9membered heterocyclic ring which may be optionally substituted by one ormore of R¹⁶; L and R¹⁷ may be taken together to form a 3 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶; L and R¹⁸ may be taken together to form a 4 to 9membered alicyclic or heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹⁷ and R¹⁸ and may be taken togetherto form a 4 to 9 membered heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹⁷ and Q may be taken together toform a 3 to 9 membered alicyclic or heterocyclic ring which may beoptionally substituted by one or more of R¹⁶; R¹⁸ and Q may be takentogether to form a 4 to 9 membered heterocyclic ring which may beoptionally by one or more of R¹⁶; R¹⁷ and R²⁰ and may be taken togetherto form a 5 to 9 membered heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹⁹ is hydrogen, R¹¹, or C(O)—R¹¹;R¹¹ is selected from the group consisting of hydrogen, hydroxyl,alkenyl, alkynyl, heterocyclyl, aromatic hydrocarbon, cycloalkyl,dihydropyridyl, alkyl, alkylthiol, alkoxy, amino, and cycloalkoxy, whichmay be optionally substituted with one or more of amino, carboxyl,carboxamide, thioalkyl, aromatic hydrocarbon, alkyl, alkylaryl, hydroxy,alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, heterocyclyl,alkylheterocycle, and alkylthiol, which may be optionally substitutedwith one or more of hydroxy, amino, guanidino, iminoalkyl; R¹² isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocycle, and aromatic hydrocarbon, all may be optionallysubstituted by one or more alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, nitro, cyano, or amino groups; R²⁰ is selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, cycloalkenyl, aromatic hydrocarbon, heterocycle, alkylaryl,and alkylheterocycle, which may be optionally substituted by one or moreof halogen, haloalkyl, cyano, nitro, —CO₂R, and —COR; R²⁰ may also beselected from the group consisting of alkylhydroxy, alkylpolyhydroxy,alkyl(poly)oxyacyl, CH₂C(═O)OR¹², CH₂C(═O)NHR¹², CH₂OC(═O)R¹², andCH₂OC(═O)VR¹², wherein the CH₂ may be optionally substituted by one ormore of lower alkyl, cycloalkyl, heterocycle, aromatic hydrocarbon,amidino, guanidino, CO₂H, amino, hydroxy, thiol, halogen, haloalkyl,cyano, and nitro; V is selected from the group consisting of O, S, CH₂,CHR¹², C(R¹²)₂, NH, and NR¹²; R², R³, R⁴ are independently selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substitutions maybe optionally substituted with one or more of the group consisting oflower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lowerthioalkoxy, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, andguanidino; G is selected from the group consisting of NR⁵, O, S, SO,SO₂, (CH₂)_(p), and CH═CH, wherein p is 0 to 6; A is selected from thegroup consisting of NR⁵, O, S, SO, SO₂, (CH₂)_(q), and CH═CH, q is 0 to6; B is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(v), and CH═CH. v is 0 to 6; R¹ and R² may optionally be takentogether to form an alicyclic hydrocarbon, heterocyclyl or aromatichydrocarbon and said optionally formed ring may be optionallysubstituted with one or more selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino; R² and R³ may optionally be taken together to form analicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and saidoptionally formed ring may be optionally substituted with one or moreselected from the group consisting of, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl,acylamino, carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino, wherein all said substitutions may be optionally substitutedwith one or more of the group consisting of lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy,lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, and guanidino. L and Q are independentlyselected from the group consisting of lower alkylene, lower alkenylene,lower alkynylene, heterocyclyl, cycloalkyl, aromatic hydrocarbon, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen, nitro, cyano,haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl,lactamyl, amidino, isourea, isothiourea, guanidino, and substitutedguanidino; k is 0 to 8; m is 0 to 7; n is 0 to 5; M is selected from thegroup consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, SeO₂, C(O)NR¹³, and SiE₂, wherein R¹³ is selectedfrom the group consisting of hydrogen, lower alkyl, alkaryl,heterocyclyl, COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatichydrocarbon; E is lower alkyl or aryl; L and R² may be taken together toform a lower alkylidene; R⁵ is selected from the group consisting ofhydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl,wherein all said substituents may be optionally substituted by one ormore carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, alkoxy, and aryloxyl; X is selected from the groupconsisting of O, S, C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂; Yis a bond, or is selected from the group consisting of O, S, C(═O),C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂; Z is selected from the groupconsisting of O, S, C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂. 2.A compound as recited in claim 1 and salts, pharmaceutically acceptableesters, and prodrugs thereof, wherein: R¹ is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, OR⁵,SR⁵, S(O)R⁵, S(O)₂R⁵, C(O)R⁶, carboalkoxyalkyl, heterocyclyl, aromatichydrocarbon and cycloalkyl, all of which may be optionally substitutedby one or more of the groups selected from lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro,amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl,P(R⁵)₃, C(O)R⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂R⁶, CONR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino, wherein allsaid substituents may be optionally substituted with one or moreselected from the group consisting of halogen, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷,S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), C(O)R⁶, carboalkoxyalkyl, cyano, nitro,amidino, and guanidino, wherein R⁵ and R⁶ of SO₂NR⁵R⁶ and NR⁵SO₂R⁶ maybe taken together to form a N-containing heterocycle, optionallysubstituted by one or more selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, and carboxyalkyl; R² and L may be taken together to form a 3 to9 membered alicyclic or heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹¹ is selected from the groupconsisting of hydrogen, hydroxyl, alkenyl, alkynyl, heterocyclyl,aromatic hydrocarbon, cycloalkyl, dihydropyridyl, alkyl, alkylthiol,alkoxy, amino, and cycloalkoxy, which may be optionally substituted withone or more of amino, carboxyl, carboxamide, thioalkyl, aromatichydrocarbon, alkyl, alkylaryl, hydroxy, alkoxy, halogen,trifluoromethyl, nitro, cyano, amino, heterocyclyl, alkylheterocycle,and alkylthiol, which may be optionally substituted with one or more ofhydroxy, amino, guanidino, iminoalkyl; R², R³, R⁴ are independentlyselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R⁶,carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂R⁶, CONR⁵R⁶, PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino,dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl,acylamino, carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy,cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substitutions maybe optionally substituted with one or more of the group consisting oflower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lowerthioalkoxy, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, andguanidino; G is selected from the group consisting of NR⁵, O, S, SO,SO₂, (CH₂)_(p), and CH═CH, wherein p is 0 to 6; A is selected from thegroup consisting of NR⁵, O, S, SO, SO₂, (CH₂)_(q), and CH═CH, q is 0 to6; B is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(v), and CH═CH. v is 0 to 6; R¹ and R² may optionally be takentogether to form an alicyclic hydrocarbon, heterocyclyl or aromatichydrocarbon and said optionally formed ring may be optionallysubstituted with one or more selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino; R² and R³ may optionally be taken together to form analicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and saidoptionally formed ring may be optionally substituted with one or moreselected from the group consisting of, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl,acylamino, carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino, wherein all said substitutions may be optionally substitutedwith one or more of the group consisting of lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy,lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, and guanidino. L is selected from thegroup consisting of lower alkylene, lower alkenylene, lower alkynylene,heterocyclyl, cycloalkyl, aromatic hydrocarbon, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen, nitro, cyano,haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl,lactamyl, amidino, isourea, isothiourea, guanidino, and substitutedguanidino; k is 0 to 8; m is 0 to 7; n is 0 to 5; M is selected from thegroup consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, SeO₂, C(O)NR¹³, and SiE₂, wherein R¹³ is selectedfrom the group consisting of hydrogen, lower alkyl, alkaryl,heterocyclyl, COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatichydrocarbon; E is lower alkyl or aryl; L and R² may be taken together toform a lower alkylidene; R⁵ is selected from the group consisting ofhydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl,wherein all said substituents may be optionally substituted by one ormore carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, alkoxy, and aryloxyl; X is selected from the groupconsisting of O, S, C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂; Yis a bond, or is selected from the group consisting of O, S, C(═O),C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂; Z is selected from the groupconsisting of O, S, C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂. 3.A compound recited in claim 2 and salts, pharmaceutically acceptableesters, and prodrugs thereof, wherein: R¹ is selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, OR⁵,SR⁵, S(O)R⁵, S(O)₂R⁵, C(O)R⁶, carboalkoxyalkyl, heterocyclyl, aromatichydrocarbon and cycloalkyl, all of which may be optionally substitutedby one or more of the groups selected from lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro,amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl,P(R⁵)₃, C(O)R⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂R⁶, CONR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino, wherein allsaid substituents may be optionally substituted with one or moreselected from the group consisting of halogen, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷,S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), C(O)R⁶, carboalkoxyalkyl, cyano, nitro,amidino, and guanidino, wherein R⁵ and R⁶ of SO₂NR⁵R⁶ and NR⁵SO₂R⁶ maybe taken together to form a N-containing heterocycle, optionallysubstituted by one or more selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, and carboxyalkyl; R² and L may be taken together to form a 3 to9 membered alicyclic or heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R², R³, R⁴ are independently selectedfrom the group consisting of hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substitutions maybe optionally substituted with one or more of the group consisting oflower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lowerthioalkoxy, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, andguanidino; G is selected from the group consisting of NR⁵, O, S,(CH₂)_(p), and CH═CH, wherein p is 0 to 3; A is selected from the groupconsisting of NR⁵, O, S, (CH₂)_(q), and CH═CH, q is 0 to 3; B isselected from the group consisting of NR⁵, O, S, SO, SO₂, (CH₂)_(v), andCH═CH. v is 0 to 6; R² and R³ may optionally be taken together to forman alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and saidoptionally formed ring may be optionally substituted with one or moreselected from the group consisting of, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl,acylamino, carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino, wherein all said substitutions may be optionally substitutedwith one or more of the group consisting of lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy,lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, and guanidino; L is selected from thegroup consisting of lower alkylene, lower alkenylene, lower alkynylene,heterocyclyl, cycloalkyl, aromatic hydrocarbon, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen, nitro, cyano,haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl,lactamyl, amidino, isourea, isothiourea, guanidino, and substitutedguanidino; k is 0 to 8; m is 0 to 7; n is 0 to 5; M is selected from thegroup consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, SeO₂, and C(O)NR¹³, wherein R¹³ is selected fromthe group consisting of hydrogen, lower alkyl, alkaryl, heterocyclyl,COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatic hydrocarbon; Land R² may be taken together to form a lower alkylidene; R⁵ is selectedfrom the group consisting of hydrogen, halogen lower alkyl, aromatichydrocarbon, and alkylaryl, wherein all said substituents may beoptionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;R⁶ is selected from the group consisting of hydrogen, lower alkyl,aromatic hydrocarbon and alkylaryl wherein all said substituents may beoptionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;R⁷ is selected from the group consisting of hydroxy, alkoxy, andaryloxyl; X is selected from the group consisting of O, S, C(═O), C(═S),S(═O), and SO₂; Y is a bond, or is selected from the group consisting ofO, S, C(═O), C(═S), S(═O), and SO₂; Z is selected from the groupconsisting of O, S, C(═O), C(═S), S(═O), and SO₂.
 4. A compound recitedin claim 3 and salts, pharmaceutically acceptable esters, and prodrugsthereof, wherein: R¹ is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower alkynyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,C(O)R⁶, carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon andcycloalkyl, all of which may be optionally substituted by one or more ofthe groups selected from lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, P(R⁵)₃,C(O)R⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶,CONR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all saidsubstituents may be optionally substituted with one or more selectedfrom the group consisting of halogen, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷,SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), C(O)R⁶, carboalkoxyalkyl, cyano, nitro, amidino,and guanidino, wherein R⁵ and R⁶ of SO₂NR⁵R⁶ and NR⁵SO₂R⁶ may be takentogether to form a N-containing heterocycle, optionally substituted byone or more selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano,nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, andcarboxyalkyl; R², R³, R⁴ are independently selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino; G is selected from the groupconsisting of (CH₂)_(p), and CH═CH, wherein p is 0 to 3; A is selectedfrom the group consisting of NR⁵, O, S, (CH₂)_(q), and CH═CH, q is 0 to3; B is selected from the group consisting of SO, SO₂, (CH₂)_(v), andCH═CH. v is 0 to 6; R² and R³ may optionally be taken together to forman alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and saidoptionally formed ring may be optionally substituted with one or moreselected from the group consisting of, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl,acylamino, carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino, wherein all said substitutions may be optionally substitutedwith one or more of the group consisting of lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy,lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, and guanidino; L is selected from thegroup consisting of lower alkylene, lower alkenylene, lower alkynylene,heterocyclyl, and —(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all saidsubstituents may optionally be substituted by one or more lower alkyl,lower alkenyl, lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen,nitro, cyano, haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino, isourea, isothiourea, guanidino, andsubstituted guanidino; k is 0 to 6; m is 0 to 7; n is 0 to 5; M isselected from the group consisting of cycloalkyl, aromatic hydrocarbon,POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵, C(O), C(O)O, Se, SeO, SeO₂, andC(O)NR¹³, wherein R¹³ is selected from the group consisting of hydrogen,lower alkyl, alkaryl, heterocyclyl, COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ islower alkyl or aromatic hydrocarbon; L and R² may be taken together toform a lower alkylidene; R⁵ is selected from the group consisting ofhydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl,wherein all said substituents may be optionally substituted by one ormore carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, alkoxy, and aryloxyl; X is selected from the groupconsisting of O, S, C(═O), C(═S); Y is a bond; Z is selected from thegroup consisting of O, S, C(═O), and C(═S).
 5. A compound recited inclaim 4 and salts, pharmaceutically acceptable esters, and prodrugsthereof, wherein: R¹ is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower alkynyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,C(O)R⁶, carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon andcycloalkyl, all of which may be optionally substituted by one or more ofthe groups selected from lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substituents maybe optionally substituted with one or more selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), C(O)R⁶, carboalkoxyalkyl, cyano, nitro, amidino, andguanidino, wherein R⁵ and R⁶ of SO₂NR⁵R⁶ and NR⁵SO₂R⁶ may be takentogether to form a N-containing heterocycle, optionally substituted byone or more selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano,nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, andcarboxyalkyl; R², R³, R⁴ are independently selected from the groupconsisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino; G is (CH₂)_(p), wherein p is 0 to3; A is selected from the group consisting of NR⁵, O, S, (CH₂)_(q), andCH═CH, q is 0 to 3; B is (CH₂)_(v), wherein v is 0 to 6; R² and R³ mayoptionally be taken together to form an alicyclic hydrocarbon,heterocyclyl or aromatic hydrocarbon and said optionally formed ring maybe optionally substituted with one or more selected from the groupconsisting of, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen,cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino; L isselected from the group consisting of lower alkylene, lower alkenylene,lower alkynylene, heterocyclyl, and —(CH₂)_(m)—M—(CH₂)_(n)—,—(CH₂)_(k)—, wherein all said substituents may optionally be substitutedby one or more lower alkyl, lower alkenyl, lower alkynyl, C(O)R⁶,carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵,heterocyclyl, halogen, nitro, cyano, haloalkyl, cycloalkyl,heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino,isourea, isothiourea, guanidino, and substituted guanidino; k is 0 to 6;m is 0 to 7; n is 0 to 5; M is selected from the group consisting ofcycloalkyl, aromatic hydrocarbon, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, SeO₂, and C(O)NR¹³, wherein R¹³ is selected fromthe group consisting of hydrogen, lower alkyl, alkaryl, heterocyclyl,COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatic hydrocarbon; R⁵is selected from the group consisting of hydrogen, halogen lower alkyl,aromatic hydrocarbon, and alkylaryl, wherein all said substituents maybe optionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;R⁶ is selected from the group consisting of hydrogen, lower alkyl,aromatic hydrocarbon and alkylaryl wherein all said substituents may beoptionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;R⁷ is selected from the group consisting of hydroxy, alkoxy, andaryloxyl; X is C(═O); Y is a bond; Z is O.
 6. A compound recited inclaim 5 and salts, pharmaceutically acceptable esters, and prodrugsthereof, wherein: R¹ is selected from the group consisting of hydrogen,lower alkyl, lower alkenyl, lower alkynyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,C(O)R⁶, carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon andcycloalkyl, all of which may be optionally substituted by one or more ofthe groups selected from lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substituents maybe optionally substituted with one or more selected from the groupconsisting of halogen, lower alkyl; R², R³, R⁴ are independentlyselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, acylamino, carboxyl, carboalkoxy, cyano,aminocarbonylamino, aminocarbonylaminoalkyl, and haloalkyl, wherein allsaid substituents may be optionally substituted by one or more selectedfrom the group consisting of hydroxy, lower alkoxy, thiol, lowerthioalkoxy, amino, lower alkyl; G is (CH₂)_(p), wherein p is 0 to 3; Ais selected from the group consisting of O, S, (CH₂)_(q), and CH═CH, qis 0 to 3; B is (CH₂)_(v), wherein v is 0 to 6; R² and R³ may optionallybe taken together to form an alicyclic hydrocarbon, heterocyclyl oraromatic hydrocarbon and said optionally formed ring may be optionallysubstituted with one or more selected from the group consisting of,amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl,CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷,SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino; L is selected from thegroup consisting of lower alkylene, lower alkenylene, lower alkynylene,heterocyclyl, and —(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all saidsubstituents may optionally be substituted by one or more lower alkyl,lower alkenyl, lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, heterocyclyl, halogen, nitro, cyano, haloalkyl, cycloalkyl,heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino,isourea, isothiourea, guanidino, and substituted guanidino; k is 0 to 6;m is 0 to 7; n is 0 to 5; M is selected from the group consisting ofcycloalkyl, aromatic hydrocarbon, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, and SeO₂; R⁵ is selected from the group consistingof hydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl,wherein all said substituents may be optionally substituted by one ormore carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, and alkoxy; X is C(═O); Y is a bond; Z is O.
 7. A compoundrecited in claim 6 and salts, pharmaceutically acceptable esters, andprodrugs thereof, wherein: R¹ is selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower alkynyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, C(O)R⁶, carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbonand cycloalkyl, all of which may be optionally substituted by one ormore of the groups selected from lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substituents maybe optionally substituted with one or more selected from the groupconsisting of halogen, lower alkyl; R², R³, R⁴ are independentlyselected from the group consisting of hydrogen, lower alkyl, C(O)R⁶,carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, halogen, amino, alkylamino,aminoalkyl, cyano, and haloalkyl; G is (CH₂)_(p), wherein p is 0 to 3; Ais selected from the group consisting of O, S, (CH₂)_(q), and CH═CH, qis 0 to 3; B is (CH₂)_(v), wherein v is 0 to 6; R² and R³ may optionallybe taken together to form an alicyclic hydrocarbon, heterocyclyl oraromatic hydrocarbon and said optionally formed ring may be optionallysubstituted with one or more selected from the group consisting of,amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl,CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷,SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino; L is selected from thegroup consisting of lower alkylene, lower alkenylene, lower alkynylene,heterocyclyl, and —(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all saidsubstituents may optionally be substituted by one or more lower alkyl,lower alkenyl, lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, heterocyclyl, halogen, nitro, cyano, and haloalkyl; k is 0 to 6;m is 0 to 7; n is 0 to 5; M is selected from the group consisting ofcycloalkyl, aromatic hydrocarbon, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, and SeO₂; R⁵ is selected from the group consistingof hydrogen, halogen lower alkyl, and aromatic hydrocarbon, wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, and alkoxy; X is C(═O); Y is a bond; Z is O.
 8. A compoundas recited in claim 1 and salts, pharmaceutically acceptable esters, andprodrugs thereof, wherein: R¹ may be

wherein J is selected from the group consisting of O, S and NR; R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aromatichydrocarbon, alkylaryl, alkylheterocycle, all of which may be optionallysubstituted by one or more of alkyl, hydroxy, alkoxy, halogen,haloalkyl, cyano, amino, and nitro; NR and R²⁰ may optionally form aheterocycle; R¹⁶ is selected from the group consisting of lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵,S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino,wherein all said substituents may be optionally substituted with one ormore of the group consisting of lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, loweralkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁸, S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂,PO(OR⁸)(OR⁹), amidino, and guanidino; R¹⁷ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, alkylaryl, andalkylheterocycle, all except hydrogen may be optionally substituted byone or more of alkyl, hydroxy, alkoxy, thiol, alkylthiol, halogen,haloalkyl, carboxyl, cyano, amino, and nitro; R¹⁸ is selected from thegroup consisting of hydrogen, hydroxyl, R¹², S(O)R¹¹, SO₂R¹¹,CH₂OC(O)—R¹¹, and C(O)—R¹¹ wherein C(O)—R¹¹; R¹⁸ and R²⁰ may be takentogether to form a 5- or 6-membered heterocyclic ring containing two ormore heteroatoms which may be optionally substituted by one or more ofR¹⁶; R² and L may be taken together to form a 3 to 9 membered alicyclicor heterocyclic ring which may be optionally substituted by one or moreof R¹⁶; R² and R¹⁷ may be taken together to form a 4 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶; R² and R¹⁸ may be taken together to form a 6 to 9membered heterocyclic ring which may be optionally substituted by one ormore of R¹⁶; L and R¹⁷ may be taken together to form a 3 to 9 memberedalicyclic or heterocyclic ring which may be optionally substituted byone or more of R¹⁶; L and R¹⁸ may be taken together to form a 4 to 9membered alicyclic or heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹⁷ and R¹⁸ and may be taken togetherto form a 4 to 9 membered heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹⁷ and Q may be taken together toform a 3 to 9 membered alicyclic or heterocyclic ring which may beoptionally substituted by one or more of R¹⁶; R¹⁸ and Q may be takentogether to form a 4 to 9 membered heterocyclic ring which may beoptionally by one or more of R¹⁶; R¹⁷ and R²⁰ and may be taken togetherto form a 5 to 9 membered heterocyclic ring which may be optionallysubstituted by one or more of R¹⁶; R¹⁹ is hydrogen, R¹¹, or C(O)—R¹¹;R¹¹ is selected from the group consisting of hydrogen, hydroxyl,alkenyl, alkynyl, heterocyclyl, aromatic hydrocarbon, cycloalkyl,dihydropyridyl, alkyl, alkylthiol, alkoxy, amino, and cycloalkoxy, whichmay be optionally substituted with one or more of amino, carboxyl,carboxamide, thioalkyl, aromatic hydrocarbon, alkyl, alkylaryl, hydroxy,alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, heterocyclyl,alkylheterocycle, and alkylthiol, which may be optionally substitutedwith one or more of hydroxy, amino, guanidino, iminoalkyl; R¹² isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocycle, and aromatic hydrocarbon, all may be optionallysubstituted by one or more alkyl, hydroxy, alkoxy, halogen,trifluoromethyl, nitro, cyano, or amino groups; R²⁰ is selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, cycloalkenyl, aromatic hydrocarbon, heterocycle, alkylaryl,and alkylheterocycle, which may be optionally substituted by one or moreof halogen, haloalkyl, cyano, nitro, —CO₂R, and —COR; R²⁰ may also beselected from the group consisting of alkylhydroxy, alkylpolyhydroxy,alkyl(poly)oxyacyl, CH₂C(═O)OR¹², CH₂C(═O)NHR¹², CH₂OC(═O)R¹², andCH₂OC(═O)VR¹², wherein the CH₂ may be optionally substituted by one ormore of lower alkyl, cycloalkyl, heterocycle, aromatic hydrocarbon,amidino, guanidino, CO₂H, amino, hydroxy, thiol, halogen, haloalkyl,cyano, and nitro; V is selected from the group consisting of O, S, CH₂,CHR¹², C(R¹²)₂, NH, and NR¹²; R², R³, R⁴ are independently selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all said substitutions maybe optionally substituted with one or more of the group consisting oflower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lowerthioalkoxy, halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, andguanidino; G is selected from the group consisting of NR⁵, O, S, SO,SO₂, (CH₂)_(p), and CH═CH, wherein p is 0 to 6; A is selected from thegroup consisting of NR⁵, O, S, SO, SO₂, (CH₂)_(q), and CH═CH, q is 0 to6; B is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(v), and CH═CH. v is 0 to 6; R² and R³ may optionally be takentogether to form an alicyclic hydrocarbon, heterocyclyl or aromatichydrocarbon and said optionally formed ring may be optionallysubstituted with one or more selected from the group consisting of,amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl,arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl,CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷,SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino, wherein all saidsubstitutions may be optionally substituted with one or more of thegroup consisting of lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy,aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂,PO(OR⁵)(OR⁶), amidino, and guanidino; L and Q are independently selectedfrom the group consisting of lower alkylene, lower alkenylene, loweralkynylene, heterocyclyl, cycloalkyl, aromatic hydrocarbon, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen, nitro, cyano,haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl,lactamyl, amidino, isourea, isothiourea, guanidino, and substitutedguanidino; k is 0 to 8; m is 0 to 7; n is 0 to 5; M is selected from thegroup consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, SeO₂, C(O)NR¹³, and SiE₂, wherein R¹³ is selectedfrom the group consisting of hydrogen, lower alkyl, alkaryl,heterocyclyl, COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatichydrocarbon; E is lower alkyl or aryl; L and R² may be taken together toform a lower alkylidene; R⁵ is selected from the group consisting ofhydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl,wherein all said substituents may be optionally substituted by one ormore carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, alkoxy, and aryloxyl; X is selected from the groupconsisting of O, S, C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂; Yis a bond, or is selected from the group consisting of O, S, C(═O),C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂; Z is selected from the groupconsisting of O, S, C(═O), C(═S), C═C(R¹¹)₂, S(═O), SO₂, and C(R¹¹)₂. 9.A compound as recited in claim 8 and salts, pharmaceutically acceptableesters, and prodrugs thereof, wherein: R¹ is

wherein J is selected from the group consisting of O, S and NR; R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aromatichydrocarbon, alkylaryl, alkylheterocycle, all of which may be optionallysubstituted by one or more of alkyl, hydroxy, alkoxy, halogen,haloalkyl, cyano, amino, and nitro; NR and R²⁰ may optionally form aheterocycle; R¹⁶ is selected from the group consisting of lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵,S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino,wherein all said substituents may be optionally substituted with one ormore of the group consisting of lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, loweralkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁸, S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂,PO(OR⁸)(OR⁹), amidino, and guanidino; R¹⁷ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, alkylaryl, andalkylheterocycle, all except hydrogen may be optionally substituted byone or more of alkyl, hydroxy, alkoxy, thiol, alkylthiol, halogen,haloalkyl, carboxyl, cyano, amino, and nitro; R¹⁸ is selected from thegroup consisting of hydrogen, hydroxyl, and R¹²; R¹⁷ and Q may be takentogether to form a 3 to 9 membered alicyclic or heterocyclic ring whichmay be optionally substituted by one or more of R¹⁶; R¹⁸ and Q may betaken together to form a 4 to 9 membered heterocyclic ring which may beoptionally by one or more of R¹⁶; R¹⁹ is hydrogen; R¹² is selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, and aromatic hydrocarbon, all may be optionally substitutedby one or more alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro,cyano, or amino groups; R²⁰ is selected from the group consisting ofhydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,cycloalkenyl, aromatic hydrocarbon, heterocycle, alkylaryl, andalkylheterocycle, which may be optionally substituted by one or more ofhalogen, haloalkyl, cyano, nitro, —CO₂R, and —COR; R², R³, R⁴ areindependently selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, aromatic hydrocarbon, heterocyclyl,C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷,SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶, PO(OR⁵)(OR⁶), halogen, nitro, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,alkylaminoaryl, acylamino, carboxyl, carboalkoxy, carboaryloxy,carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino,aminocarbonylaminoalkyl, carboxyaldehyde, and haloalkyl, wherein allsaid substituents may be optionally substituted by one or more selectedfrom the group consisting of hydroxy, lower alkoxy, aryloxy, thiol,lower thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶,lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl,aromatic hydrocarbon, halogen, cyano, nitro, C(O)NR⁵OR⁵,OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino, wherein all said substitutions may be optionally substitutedwith one or more of the group consisting of lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy,lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, and guanidino; G is selected from thegroup consisting of NR⁵, O, S, (CH₂)_(p), and CH═CH, wherein p is 0 to3; A is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(q), and CH═CH, q is 0 to 3; B is selected from the groupconsisting of NR⁵, O, S, (CH₂)_(v), and CH═CH. v is 0 to 3; R² and R³may optionally be taken together to form an alicyclic hydrocarbon,heterocyclyl or aromatic hydrocarbon and said optionally formed ring maybe optionally substituted with one or more selected from the groupconsisting of, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen,cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino, whereinall said substitutions may be optionally substituted with one or more ofthe group consisting of lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy,aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂,PO(OR⁵)(OR⁶), amidino, and guanidino; L and Q are independently selectedfrom the group consisting of lower alkylene, lower alkenylene, loweralkynylene, heterocyclyl, cycloalkyl, aromatic hydrocarbon, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen, nitro, cyano,haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl,lactamyl, amidino, isourea, isothiourea, guanidino, and substitutedguanidino; k is 0 to 8; m is 0 to 7; n is 0 to 5; M is selected from thegroup consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵,C(O), C(O)O, Se, SeO, SeO₂, and C(O)NR¹³, wherein R¹³ is selected fromthe group consisting of hydrogen, lower alkyl, alkaryl, heterocyclyl,COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatic hydrocarbon; R⁵is selected from the group consisting of hydrogen, halogen lower alkyl,aromatic hydrocarbon, and alkylaryl, wherein all said substituents maybe optionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;R⁶ is selected from the group consisting of hydrogen, lower alkyl,aromatic hydrocarbon and alkylaryl wherein all said substituents may beoptionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;R⁷ is selected from the group consisting of hydroxy, alkoxy, andaryloxyl; X is selected from the group consisting of O, S, C(═O), C(═S),S(═O), and SO₂; Y is a bond, or is selected from the group consisting ofO, S, C(═O), C(═S), S(═O), and SO₂; Z is selected from the groupconsisting of O, S, C(═O), C(═S), S(═O), and SO₂.
 10. A compound asrecited in claim 9 and salts, pharmaceutically acceptable esters, andprodrugs thereof, wherein: R¹ is

wherein J is selected from the group consisting of O, S and NR; R isselected from the group consisting of hydrogen, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aromatichydrocarbon, alkylaryl, alkylheterocycle; NR and R²⁰ may optionally forma heterocycle; R¹⁶ is selected from the group consisting of lower alkyl,lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵,S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino,wherein all said substituents may be optionally substituted with one ormore of the group consisting of lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, loweralkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁸, S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂,PO(OR⁸)(OR⁹), amidino, and guanidino; R¹⁷ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, heterocycle, and alkylheterocycle, all excepthydrogen may be optionally substituted by one or more of alkyl, hydroxy,alkoxy, thiol, alkylthiol, halogen, haloalkyl, carboxyl, cyano, amino,and nitro; R¹⁸ is selected from the group consisting of hydrogen, andhydroxyl; R¹⁸ and Q may be taken together to form a 4 to 9 memberedheterocyclic ring which may be optionally by one or more of R¹⁶; R¹⁹ ishydrogen; R²⁰ is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aromatichydrocarbon, heterocycle, alkylaryl, and alkylheterocycle, which may beoptionally substituted by one or more of halogen, haloalkyl, cyano,nitro, —CO₂R, and —COR; R², R³, R⁴ are independently selected from thegroup consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl,aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵,S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino; G is selected from the groupconsisting of (CH₂)_(p), and CH═CH, wherein p is 0 to 3; A is selectedfrom the group consisting of NR⁵, O, S, SO, SO₂, (CH₂)_(q), and CH═CH, qis 0 to 3; B is selected from the group consisting of (CH₂)_(v), andCH═CH. v is 0 to 3; R² and R³ may optionally be taken together to forman alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and saidoptionally formed ring may be optionally substituted with one or moreselected from the group consisting of, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl,acylamino, carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,halogen, cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵,S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, andguanidino, wherein all said substitutions may be optionally substitutedwith one or more of the group consisting of lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy,lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro,C(O)R⁶, carboalkoxyalkyl, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,NR⁵SO₂, PO(OR⁵)(OR⁶), amidino, and guanidino; Q is —(CH₂)_(k)—, whereink is
 0. L is selected from the group consisting of lower alkylene, loweralkenylene, lower alkynylene, heterocyclyl, and —(CH₂)_(m)—M—(CH₂)_(n)—,—(CH₂)_(k)—, wherein all said substituents may optionally be substitutedby one or more lower alkyl, lower alkenyl, lower alkynyl, C(O)R⁶,carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵,heterocyclyl, halogen, nitro, cyano, haloalkyl, cycloalkyl,heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino,isourea, isothiourea, guanidino, and substituted guanidino; k is 0 to 6;m is 0 to 5; n is 0 to 3; M is selected from the group consisting ofcycloalkyl, heterocyclyl, aromatic hydrocarbon, O, S, SO, SO₂, SO₂NR⁵,NR⁵SO₂, NR⁵, POOR⁵, PON(R⁵)₂, POOR⁵NR⁵, NR⁵POOR⁵, C(O), C(O)O, Se, SeO,SeO₂, and C(O)NR¹³, wherein R¹³ is selected from the group consisting ofhydrogen, lower alkyl, alkaryl, heterocyclyl, COR¹⁴, and CO₂R¹⁴ whereinR¹⁴ is lower alkyl or aromatic hydrocarbon; R⁵ is selected from thegroup consisting of hydrogen, halogen lower alkyl, aromatic hydrocarbon,and alkylaryl, wherein all said substituents may be optionallysubstituted by one or more carboalkoxy, thiol, amino, hydroxyl,carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro,carboxyalkyl, carboxamides, phosphonates, and sulfonates; R⁶ is selectedfrom the group consisting of hydrogen, lower alkyl, aromatic hydrocarbonand alkylaryl wherein all said substituents may be optionallysubstituted by one or more carboalkoxy, thiol, amino, hydroxyl,carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro,carboxyalkyl, carboxamides, phosphonates, and sulfonates; R⁷ is selectedfrom the group consisting of hydroxy, alkoxy, and aryloxyl; X isselected from the group consisting of O, S, C(═O),and C(═S); Y is abond; Z is selected from the group consisting of O, S, C(═O), and C(═S).11. A compound as recited in claim 10 and salts, pharmaceuticallyacceptable esters, and prodrugs thereof, wherein: R¹ is

wherein J is O; R¹⁶ is selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵,S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino,wherein all said substituents may be optionally substituted with one ormore of the group consisting of lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, loweralkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁸, S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂,PO(OR⁸)(OR⁹), amidino, and guanidino; R¹⁷ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, and heterocycle, all except hydrogen may beoptionally substituted by one or more of alkyl, hydroxy, alkoxy, thiol,alkylthiol, halogen, haloalkyl, carboxyl, cyano, amino, and nitro; R¹⁸is hydrogen; R¹⁹ is hydrogen; R²⁰ is selected from the group consistingof hydrogen, and lower alkyl; R², R³, R⁴ are independently selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl, loweralkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R⁶, carboalkoxyalkyl,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, NR⁵SO₂R⁶, CONR⁵R⁶,PO(OR⁵)(OR⁶), halogen, nitro, amino, alkylamino, dialkylamino,aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino,carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano,aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl,carboxyaldehyde, and haloalkyl, wherein all said substituents may beoptionally substituted by one or more selected from the group consistingof hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino,aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R⁶,carboalkoxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano,nitro, C(O)NR⁵OR⁵,OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶,PO(OR⁵)(OR⁶), amidino, and guanidino; G is (CH₂)_(p), wherein p is 0 to3; A is selected from the group consisting of NR⁵, O, S, SO, SO₂,(CH₂)_(q), and CH═CH, q is 0 to 3; B is (CH₂)_(v), wherein v is 0 to 3;R² and R³ may optionally be taken together to form an alicyclichydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionallyformed ring may be optionally substituted with one or more selected fromthe group consisting of, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, CONR⁵R⁶, NR⁵SO₂R⁶, lower alkyl, lower alkenyl,lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen,cyano, nitro, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,S(O)R⁷, S(O)₂R⁷, SO₂NR⁵R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino; Q is—(CH₂)_(k)—, wherein k is
 0. L isselected from the group consisting oflower alkylene, lower alkenylene, lower alkynylene, heterocyclyl, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,SO₂NR⁵R⁶, NR⁵SO₂R⁶, C(O)R⁵, heterocyclyl, halogen, nitro, cyano,haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl,lactamyl, amidino, isourea, isothiourea, guanidino, and substitutedguanidino; k is 0 to 6; m is 0 to 5; n is 0 to 3; M is selected from thegroup consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, C(O), C(O)O, and C(O)NR¹³, wherein R¹³is selected from the group consisting of hydrogen, lower alkyl, alkaryl,heterocyclyl, COR¹⁴, and CO₂R¹⁴ wherein R¹⁴ is lower alkyl or aromatichydrocarbon; R⁵ is selected from the group consisting of hydrogen,halogen lower alkyl, aromatic hydrocarbon, and alkylaryl, wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁶ is selected from the group consistingof hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein allsaid substituents may be optionally substituted by one or morecarboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; R⁷ is selected from the group consistingof hydroxy, alkoxy, and aryloxyl; X is C(═O); Y is a bond; Z is O.
 12. Acompound as recited in claim 11 and salts, pharmaceutically acceptableesters, and prodrugs thereof, wherein: R¹ is

wherein J is O; R¹⁶ is selected from the group consisting of loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatichydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy,halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl,dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino,carboxy, carboxyalkyl, C(O)R⁶, carboalkoxyalkyl, CONR⁵R⁶, S(O)R⁵,S(O)₂R⁵, SO₂NR⁵R⁶, NR⁵SO₂R⁶, PO(OR⁵)(OR⁶), amidino, and guanidino,wherein all said substituents may be optionally substituted with one ormore of the group consisting of lower alkyl, lower alkenyl, loweralkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, loweralkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R⁶,carboalkoxyalkyl, S(O)R⁸, S(O)₂R⁸, S(O)R¹⁰, S(O)₂R¹⁰, SO₂NR⁸R⁹, NR⁸SO₂,PO(OR⁸)(OR⁹), amidino, and guanidino; R¹⁷ is selected from the groupconsisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl,haloalkyl, cycloalkyl, and heterocycle, all except hydrogen may beoptionally substituted by one or more of alkyl, hydroxy, alkoxy, thiol,alkylthiol, halogen, haloalkyl, carboxyl, cyano, amino, and nitro; R¹⁸is hydrogen; R¹⁹ is hydrogen; R²⁰ is selected from the group consistingof hydrogen, and lower alkyl; R², R³, R⁴ are independently selected fromthe group consisting of hydrogen, lower alkyl, lower alkenyl, loweralkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, halogen, nitro, amino,alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, acylamino,carboxyl, carboalkoxy, cyano, aminocarbonylamino,aminocarbonylaminoalkyl, and haloalkyl, wherein all said substituentsmay be optionally substituted by one or more selected from the groupconsisting of hydroxy, lower alkoxy, thiol, lower thioalkoxy, amino; Gis (CH₂)_(p), wherein p is 0 to 3; A is selected from the groupconsisting of O, S, SO, SO₂, (CH₂)_(q), and CH═CH, q is 0 to 3; B is(CH₂)_(v), wherein v is 0 to 3; Q is —(CH₂)_(k)—, wherein k is 0; L isselected from the group consisting of lower alkylene, lower alkenylene,lower alkynylene, heterocyclyl, and —(CH₂)_(m)—M—(CH₂)_(n)—,—(CH₂)_(k)—, wherein all said substituents may optionally be substitutedby one or more lower alkyl, lower alkenyl, lower alkynyl, C(O)R⁶,carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵, heterocyclyl, halogen,nitro, cyano, haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon,lactonyl, lactamyl, amidino, isourea, isothiourea, guanidino, andsubstituted guanidino; k is 0 to 6; m is 0 to 5; n is 0 to 3; M isselected from the group consisting of cycloalkyl, heterocyclyl, aromatichydrocarbon, O, S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, NR⁵, C(O), and C(O)O; R⁵ isselected from the group consisting of hydrogen, halogen lower alkyl,aromatic hydrocarbon, and alkylaryl, wherein all said substituents maybe optionally substituted by one or more carboalkoxy, thiol, amino,hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo,cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;X is C(═O); Y is a bond; Z is O.
 13. A compound as recited in claim 12and salts, pharmaceutically acceptable esters, and prodrugs thereof,wherein: R¹ is

wherein J is O; R¹⁷ is selected from the group consisting of hydrogen,lower alkyl, and hydroxyalkyl; R¹⁸ is hydrogen; R¹⁹ is hydrogen; R²⁰ isselected from the group consisting of hydrogen, and lower alkyl; R², R³,R⁴ are independently selected from the group consisting of hydrogen,lower alkyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, halogen, amino,alkylamino, and aminoalkyl; G is (CH₂)_(p), wherein p is 0 to 3; A isselected from the group consisting of O, S, SO, SO₂, (CH₂)_(q), andCH═CH, q is 0 to 3; B is (CH₂)_(v), wherein v is 0 to 3; Q is—(CH₂)_(k)—, wherein k is 0; L is selected from the group consisting oflower alkylene, lower alkenylene, lower alkynylene, heterocyclyl, and—(CH₂)_(m)—M—(CH₂)_(n)—, —(CH₂)_(k)—, wherein all said substituents mayoptionally be substituted by one or more lower alkyl, lower alkenyl,lower alkynyl, C(O)R⁶, carboalkoxyalkyl, OR⁵, SR⁵, S(O)R⁵, S(O)₂R⁵,heterocyclyl, halogen, cyano, and haloalkyl; k is 0 to 6; m is 0 to 5; nis 0 to 3; M is selected from the group consisting of heterocyclyl, O,S, SO, SO₂, SO₂NR⁵, NR⁵SO₂, and NR⁵; R⁵ is selected from the groupconsisting of hydrogen, halogen lower alkyl, and aromatic hydrocarbon,wherein all said substituents may be optionally substituted by one ormore carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, loweralkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides,phosphonates, and sulfonates; X is C(═O); Y is a bond; Z is O.
 14. Acompound as recited in claim 1, wherein the compound is selected fromthe group consisting of(2S,3Z)-2-amino-5-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-3-pentenoicacid;a-amino-4,5,5a,6,7,8,9,9a-octahydro-5-methyl-1-oxo-1H-[1,2,4]oxadiazolo[4,3-a]quinoline-8-propanoicacid;N-[(1,1-dimethylethoxy)carbonyl]-3-[[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]amino]-L-alanine;N-[(1,1-dimethylethoxy)carbonyl]-3-[ethyl[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]amino]-L-alanine;phenylmethyl (2S,4Z)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-pentenoate;a-amino-5-fluoro-6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-hexanoicacid;N-[(1,1-dimethylethoxy)carbonyl]-S-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-L-cysteine;S-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-L-cysteine,monohydrochloride;3-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]sulfinyl]-L-alanine,monohydrochloride;3-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]sulfonyl]-L-alanine;methyla-(acetylamino)-6,7,8,9-tetrahydro-g,3-dioxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate;methyla-(acetylamino)-g,g-difluoro-6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate;methyla-(acetylamino)-6,7,8,9-tetrahydro-g-nitro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate;methyl a-(acetylamino)-6,7,8,9-tetrahydro-g-methylene-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepine-5-pentanoate;N-[(1,1-dimethylethoxy)carbonyl]-3-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]amino]-L-alanine;methyl(2S,4Z)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-6-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-hexenoate;(3Z)-2-amino-6-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-hexenoicacid;a-amino-6,7-dihydro-3-oxo-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazole-5-pentanoicacid;a-amino-6,7-dihydro-3-oxo-6-(trifluoromethyl)-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazole-5-pentanoicacid;a-amino-5-(6,7-dihydro-3-oxo-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazol-5-yl)-2-furanaceticacid;a-amino-3-(6,7-dihydro-3-oxo-3H,5H-pyrrolo[2,1-c][1,2,4]oxadiazol-5-yl)-2-benzeneaceticacid;a-amino-4,5,5a,6,7,8,9,9a-octahydro-5-methyl-1-oxo-1H-[1,2,4]-oxadiazolo[4,3-a]quinoline-9-butanoicacid; 5-amino-2-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-1H-imidazole-4-carboxylic acid,monohydrochloride;a-amino-6,7,8,9-tetrahydro-e-1H-imidazol-2-yl-3-oxo-3H,5H-[1,2,4]-oxadiazolo[4,3-a]azepine-5-hexanoicacid; phenylmethyl(2S,4Z)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-6-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)-4-hexenoate;3-[ethyl[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]amino]-L-alanine;(2S)-2-[[(phenylmethoxy)carbonyl]amino]-4-[[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)carbonyl]amino]butanoicacid;N-[(phenylmethoxy)carbonyl]-O-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]-L-serine;bis(1,1-dimethylethyl)4-nitro-4-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]heptanedioate;S-[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]homocysteine;S-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]-L-cysteine;S-[2-(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)ethyl]homocysteine;andN-[(1,1-dimethylethoxy)carbonyl]-3-[ethyl[(6,7,8,9-tetrahydro-3-oxo-3H,5H-[1,2,4]oxadiazolo[4,3-a]azepin-5-yl)methyl]amino]-L-alanine.15. A compound as recited in claim 1 wherein the compound is selectedfrom the group consisting of Example 1 through
 42. 16. A compound asrecited in claim 1 wherein the compound is selected from the groupconsisting of Example 125 through
 157. 17. A pharmaceutical compositioncomprising a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15 or 16 and together with at least one non-toxic pharmaceuticalacceptable carrier.
 18. A method of inhibiting nitric oxide synthase ina subject in need of such inhibition by administering a therapeuticallyeffective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15 or
 16. 19. A method of selectively inhibiting nitricoxide synthesis produced by inducible NO synthase over NO produced bythe constitutive forms of NO synthase in a subject in need of suchinhibition by administering a therapeutically effective amount of acompound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or16.
 20. A method of lowering nitric oxide levels in a subject in need ofsuch by administering a therapeutically effective amount of a compoundof claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or
 16. 21. Amethod of lowering nitric oxide levels in a subject in need of such byadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15 or 16 and together with at least one non-toxicpharmaceutical acceptable carrier.